Management of patients with nephrotic syndrome.
Management of patients with renal arterial
hypertension.
1. Management of
the nephrotic syndrome.
The treatment of nephrotic syndrome involves (1) specific
treatment of the underlying morphologic entity and, when possible, causative
disease; (2) general measures to control proteinuria if remission is not
achieved through immunosuppressive therapy and other specific measures; and (3)
general measures to control nephrotic complications.
A.
Protein loss:
Moderate protein restriction (0.5-0.6 g/kg/d) is
often employed. Restriction is often advocated since increased protein intake
may have an adverse effect on renal function in some diseases. The daily total
dietary protein intake should replace the dietary urinary protein losses so as
to avoid negative nitrogen balance. Protein malnutrition often occurs with
urinary protein losses greater than 10 g/d.
B.
Edema:
Dietary salt restriction is essential for managing edema; however, most
patients also require diuretic therapy. Commonly used diuretics include
thiazide and loop diuretics. Both are highly protein-bound. With
hypoalbuminemia, diuretic delivery to the kidney is reduced, and patients often
require large doses. The combination of loop and thiazide diuretica can
potentiate the diuretic effect. This may be needed for patients with refractory
fluid retention associated with pleural effusions and ascites.
C.
Hyperlipidemia:
Hypercholesterolemia and hypertriglyceridemia occur as outlined above.
Dietary management in patients with nephrotic syndrome is of little value;
however, dietary modification and exercise should be advocated. Pharmacologic
intervention is most successful with HMG-CoA reductase inhibitors.
D.
Hypercoagulable state:
Patients with serum albumin less 2 g/dL can become hypercoagulable.
Nephrotic patients have urinary losses of antithrombin III, protein C, and
protein S and increased platelet activation. Patients are prone to renal vein
thrombosis and other venous thromboemboli. Anticoagulation therapy is warranted
for at least 3-6 months in patients with evidence of thrombosis. Patients with
renal vein thrombosis and recurrent thromboemboli probably require lifetime
anticoagulation.
Pathogenesis of the nephrotic proteinuria.
The nephrotic syndrome is a clinical complex characterized by a number
of renal and extrarenal features, the most prominent of which are proteinuria
of >
Pathogenesis of the nephrotic hypoalbuminemia.
Hypoalbuminemia in nephrotic syndrome occurs through excessive urinary
losses, increased renal catabolism, and inadequate hepatic synthesis. The
resulting decrease in plasma oncotic pressure contributes to edema formation by
altering the Starling forces and favoring fluid movement from capillaries to
interstitium. The resulting homeostatic mechanisms designed to correct the
decrease in effective intravascular volume contribute to edema formation in some
patients.
Pathogenesis of
the nephrotic hyperlipidemia.
Hyperlipidemia is believed to be a consequence of increased hepatic
lipoprotein synthesis that is triggered by reduced oncotic pressure and may be
compounded by increased urinary loss of proteins that regulate lipid
homeostasis. Low-density lipoproteins and cholesterol are increased in the
majority of patients, whereas very low density lipoproteins and triglycerides
tend to rise in patients with severe disease. Although not proven conclusively,
hyperlipidemia may accelerate atherosclerosis and progression of renal disease.
Others methabolic changes.
Other metabolic complications of nephrotic syndrome include protein
malnutrition and iron-resistant microcytic hypochromic anemia due to
transferrin loss. Hypocalcemia and secondary hyperparathyroidism can occur as a
consequence of vitamin D deficiency due to enhanced urinary excretion of
cholecalciferol-binding protein, whereas loss of thyroxine-binding globulin can
result in depressed thyroxine levels. An increased susceptibility to infection
may reflect low levels of IgG that result from urinary loss and increased
catabolism. In addition, patients are prone to unpredictable changes in the
pharmacokinetics of therapeutic agents that are normally bound to plasma
proteins.
Other proteins are lost in the urine, leading to a variety of metabolic
disturbances. These include thyroxine-binding globulin, cholecalciferol-binding
protein, transferrin, and metal-binding proteins. A hypercoagulable state
frequently accompanies severe nephrotic syndrome due to urinary losses of
antithrombin III, reduced serum levels of proteins S and C,
hyperfibrinogenemia, and enhanced platelet aggregation. Some patients develop
severe IgG deficiency with resulting defects in immunity.
Hypercoagulability is probably multifactorial in origin and is caused,
at least in part, by increased urinary loss of antithrombin III, altered levels
and/or activity of proteins C and S, hyperfibrinogenemia due to increased hepatic
synthesis, impaired fibrinolysis, and increased platelet aggregability. As a
consequence of these perturbations, patients can develop spontaneous peripheral
arterial or venous thrombosis, renal vein thrombosis, and pulmonary embolism.
Clinical features that suggest acute renal vein thrombosis include sudden onset
of flank or abdominal pain, gross hematuria, a left-sided varicocele (the left
testicular vein drains into the renal vein), increased proteinuria, and an
acute decline in GFR. Chronic renal vein thrombosis is usually asymptomatic.
Renal vein thrombosis is particularly common (up to 40%) in patients with
nephrotic syndrome due to membranous glomerulopathy, membranoproliferative
glomerulonephritis, and amyloidosis.
Classification of the nephrotic syndrome.
Nephrotic syndrome can complicate any disease that perturbs the negative
electrostatic charge or architecture of the GBM and the podocytes and their
slit diaphragms. Six entities account for greater than 90% of cases of
nephrotic syndrome in adults: minimal change disease (MCD), focal and segmental
glomerulosclerosis (FSGS), membranous glomerulopathy, MPGN, diabetic
nephropathy, and amyloidosis. Diabetic nephropathy and amyloidosis, being
manifestations of systemic diseases. Renal biopsy is a valuable tool in adults
with nephrotic syndrome for establishing a definitive diagnosis, guiding
therapy, and estimating prognosis. Renal biopsy is not required in the majority
of children with nephrotic syndrome as most cases are due to MCD and respond to
empiric treatment with glucocorticoids.
Clinic manifestation of the nephrotic syndrome and pathogenesis of the
nephrotic edema.
Patients present with gradually increasing generalised oedema which
first involves subcutaneous tissue and later serous sacs. The face is
characteristically pale and puffy. General health may remain good, but
eventually is progressively impaired, with increased liability to infection of
the oedematous tissues or serous cavities. Protein malnutrition may occur. The
course and prognosis depends on the underlying renal lesion, which can only be
determined by renal biopsy.
The severity of edema correlates with the degree of hypoalbuminemia and
is modified by other factors such as heart disease or peripheral vascular
disease. The diminished plasma oncotic pressure and urinary losses of
regulatory proteins appear to stimulate hepatic lipoprotein synthesis. The
resulting hyperlipidemia results in lipid bodies (fatty casts, oval fat bodies)
in the urine.
In general, the greater the proteinuria, the lower the serum albumin
level. Hypoalbuminemia is compounded further by increased renal catabolism and
inadequate, albeit usually increased, hepatic synthesis of albumin.
The pathophysiology of edema formation in nephrotic syndrome is poorly
understood. The underfilling hypothesis postulates that hypoalbuminemia results
in decreased intravascular oncotic pressure, leading to leakage of
extracellular fluid from blood to the interstitium. Intravascular volume falls,
thereby stimulating activation of the renin-angiotensin-aldosterone axis and
the sympathetic nervous system and release of vasopressin (antidiuretic
hormone), and suppressing atrial natriuretic peptide release. These neural and
hormonal responses promote renal salt and water retention, thereby restoring
intravascular volume and triggering further leakage of fluid to the
interstitium. This hypothesis does not, however, explain the occurrence of
edema in many patients in whom plasma volume is expanded and the
renin-angiotensin-aldosterone axis is suppressed. The latter finding suggests
that primary renal salt and water retention may also contribute to edema
formation in some cases.
Complications of the nephrotic syndrome.
Complications of nephrotic syndrome that may require treatment include edema,
hyperlipidemia, thromboembolism, malnutrition, and vitamin D deficiency.
Patients can experience dyspnea due to pulmonary edema, pleural
effusions, and diaphragmatic compromise with ascites. Complaints of abdominal
fullness may also be present in patients with ascites. Patients may show signs
and symptoms of infection more frequently than general population owing to loss
of immunoglobulins and certain complement moieties in the urine.
MINIMAL CHANGE DISEASE (MCD) also called nil disease, lipoid
nephrosis, or foot process disease) is so named because glomerular size and
architecture are normal by light microscopy. Immunofluorescence studies are
typically negative for immunoglobulin and C3. Mild mesangial hypercellularity
and sparse deposits of C3 and IgM may be detected. Occasionally, mesangial
proliferation is associated with scanty IgA deposits, similar to those found in
IgA nephropathy.
GN
with minimum changes.
TREATMENT
MCD is highly steroid-responsive and carries an
excellent prognosis. Spontaneous remission occurs in 30 to 40% of childhood
cases but is less common in adults. Approximately 90% of children and 50% of
adults enter remission following 8 weeks of high-dose oral glucocorticoids. In
a typical regimen using prednisone, children receive 60 mg/m2 of body surface
area daily for 4 weeks, followed by 40 mg/m2 on alternate days for an
additional 4 weeks; adults receive 1 to 1.5 mg/kg body weight per day for 4
weeks, followed by 1 mg/kg per day on alternate days for 4 weeks. Up to 90% of
adults enter remission if therapy is extended for 20 to 24 weeks. Nephrotic
syndrome relapses in over 50% of cases following withdrawal of glucocorticoids.
Alkylating agents are reserved for the small number of patients who fail to
achieve lasting remission. These include patients who relapse during or shortly
after withdrawal of steroids (steroid-dependent) and those who relapse more
than three times per year (frequently relapsing). In these settings,
cyclophosphamide (2 to 3 mg/kg per day) or chlorambucil (0.1 to 0.2 mg/kg per day)
is started after steroid-induced remission and continued for 8 to 12 weeks.
Cytotoxic agents may also induce remission in occasional steroid-resistant
cases. These benefits must be balanced against the risk of infertility,
cystitis, alopecia, infection, and secondary malignancies, particularly in
children and young adults. Azathioprine has not been proven to be a useful
adjunct to steroid therapy. Cyclosporine induces remission in 60 to 80% of
patients; it is an alternative to cytotoxic agents and an option in patients
who are resistant to cytotoxic agents. Unfortunately, relapse is usual when
cyclosporine is withdrawn, and long-term therapy carries the risk of
nephrotoxicity and other side effects. Long-term renal and patient survival is
excellent in MCD.
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS WITH HYALINOSIS
In contrast to MCD, spontaneous remission of primary FSGS is rare and
renal prognosis is relatively poor. Proteinuria remits in only 20 to 40% of
patients treated with glucocorticoids for 8 weeks. Uncontrolled studies suggest
that up to 70% respond when steroid therapy is prolonged for 16 to 24 weeks.
Cyclophosphamide and cyclosporine, when used at doses described above for MCD,
induce partial or complete remission in 50 to 60% of steroid-responsive
patients but are generally ineffective in steroid-resistant cases. Poor
prognostic factors at presentation include hypertension, abnormal renal
function, black race, and persistent heavy proteinuria. Renal transplantation
is complicated by recurrence of FSGS in the allograft in about 50% of cases and
graft loss in about 10%. Factors associated with an increased risk of
recurrence include a short time interval between the onset of the FSGS and
ESRD, young age at onset, and possibly the presence of mesangial
hypercellularity on renal biopsy.
FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS WITH HYALINOSIS
MEMBRANOUS
GLOMERULOPATHY
This lesion is a leading cause of idiopathic
nephrotic syndrome in adults (30 to 40%) and a rare cause in children (<5%).
Nephrotic syndrome remits spontaneously and completely in up to 40% of patients
with membranous glomerulopathy. The natural history of another 30 to 40% is
characterized by repeated relapses and remissions. The final 10 to 20% suffer a
slow progressive decline in GFR that typically culminates in ESRD after 10 to
15 years. Presenting features that predict a poor prognosis include male
gender, older age, hypertension, severe proteinuria and hyperlipidemia, and
impaired renal function. Controlled trials of glucocorticoids have failed to
show consistent improvement in proteinuria or renal protection.
Cyclophosphamide, chlorambucil, and cyclosporine have each been shown to reduce
proteinuria and/or slow the decline in GFR in patients with progressive disease
in small or uncontrolled studies. These observations need to be confirmed in
controlled prospective studies. Transplantation is a successful treatment
option for patients who reach ESRD.
MEMBRANOUS GLOMERULOPATHY
TREATMENT
Nephrotic Syndrome and Complications. The
treatment of nephrotic syndrome involves (1) specific treatment of the
underlying morphologic entity and, when possible, causative disease; (2)
general measures to control proteinuria if remission is not achieved through
immunosuppressive therapy and other specific measures; and (3) general measures
to control nephrotic complications.
General measures may be warranted to control
proteinuria in nephrotic syndrome if patients do not respond to immunosuppressive
therapy and other specific measures and suffer progressive renal failure or
severe nephrotic complications. Nonspecific measures that may reduce
proteinuria include angiotensin-converting enzyme (ACE) inhibitors, and NSAIDs.
The first of these measures aim to reduce proteinuria and slow the rate of
progression of renal failure by lowering intraglomerular pressure and
preventing the development of hemodynamically mediated focal segmental
glomerulosclerosis. There is conclusive evidence that ACE inhibitors are
renoprotective in human diabetic nephropathy and that ACE inhibitors slow the
development of secondary FSGS in experimental animals. Their role in the
treatment of nephrotic syndrome in other settings is unproven. NSAIDs also
reduce proteinuria in some patients with nephrotic syndrome, probably by
altering glomerular hemodynamics and GBM permeability characteristics. This
potential benefit must be balanced against the risk of inducing acute renal
failure, hyperkalemia, salt and water retention, and other side effects.
Complications of nephrotic syndrome that may require treatment include
edema, hyperlipidemia, thromboembolism, malnutrition, and vitamin D deficiency.
Edema should be managed cautiously by moderate salt restriction, usually 1 to 2
g/day, and the judicious use of loop diuretics. It is unwise to remove >
2. Treatment of the immune-inflammatory renal diseases
(glomerulonephritis).
2.1. Dietotherapy.
Edema should be managed cautiously by moderate
salt restriction, usually 1 to 2 g/day, and the judicious use of loop
diuretics. It is unwise to remove >
High-protein diets to prevent protein
malnutrition are now in disfavor, since protein supplements have little, if
any, effect on serum albumin levels and may hasten the progression of renal
disease by increasing urinary protein excretion. The potential value of dietary
protein restriction for reducing proteinuria must be balanced against the risk
of contributing to malnutrition.
2.2. Diuretics.
Commonly used diuretics include thiazide and loop
diuretics. Both are highly protein-bound. With hypoalbuminemia, diuretic
delivery to the kidney is reduced, and patients often require large doses. The
combination of loop and thiazide diuretica can potentiate the diuretic effect.
This may be needed for patients with refractory fluid retention associated with
pleural effusions and ascites.
Diuretics and antihypertensive agents are
employed to control extracellular fluid volume and blood pressure in
poststreptococcal glomerulonephritis
2.3, 2.4. Glucocorticoid. Immunosuppressive therapy.
Antiglomerular Basement Membrane Disease Anti-GBM.
Prior to the introduction of immunosuppressive
therapy, greater than 80% of patients with anti-GBM nephritis developed ESRD
within 1 year, and many patients died from pulmonary hemorrhage or
complications of uremia. With early and aggressive use of plasmapheresis,
glucocorticoids, cyclophosphamide, and azathioprine, renal and patient survival
have improved dramatically. In general, emergency plasmapheresis is performed
daily or on alternate days until anti-GBM antibodies are not detected in the
circulation (usually 1 to 2 weeks). Prednisone (1 mg/kg per day) is started
simultaneously, in combination with either cyclophosphamide (2 to 3 mg/kg per
day) or azathioprine (1 to 2 mg/kg per day) to suppress new synthesis of
anti-GBM antibodies.
MINIMAL
CHANGE DISEASE. MCD is highly steroid-responsive and carries an excellent prognosis.
Spontaneous remission occurs in 30 to 40% of childhood cases but is less common
in adults. Approximately 90% of children and 50% of adults enter remission
following 8 weeks of high-dose oral glucocorticoids. In a typical regimen using
prednisone, children receive 60 mg/m2 of body surface area daily for 4 weeks,
followed by 40 mg/m2 on alternate days for an additional 4 weeks; adults
receive 1 to 1.5 mg/kg body weight per day for 4 weeks, followed by 1 mg/kg per
day on alternate days for 4 weeks. Up to 90% of adults enter remission if
therapy is extended for 20 to 24 weeks. Nephrotic syndrome relapses in over 50%
of cases following withdrawal of glucocorticoids.
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS WITH HYALINOSIS
In contrast
to MCD, spontaneous remission of primary FSGS is rare and renal prognosis is
relatively poor. Proteinuria remits in only 20 to 40% of patients treated with
glucocorticoids for 8 weeks. Uncontrolled studies suggest that up to 70%
respond when steroid therapy is prolonged for 16 to 24 weeks. Focal Segmental
Glomerulosclerosis
Picture1 shows the
frequency of focal segmental glomerulosclerosis (FSGS) in adults with nephrotic
range proteinuria. FSGS accounts for about 15% to 20% of the nephrotic syndrome
in older children as well. The frequency of FSGS in a given population of
patients with the nephrotic syndrome is influenced by the racial composition of
the population, because FSGS is more common in blacks than whites.
Compared to minimal change
glomerulopathy and membranous glomerulopathy, FSGS is a difficult category of
glomerular disease to diagnose pathologically. It is probably the most
difficult category for a renal pathologist and nephrologist to deal with. There
is great confusion about how to define FSGS pathologically. There is
disagreement about how many categories of glomerular disease to put into this
rather descriptive sounding category of glomerular disease. I break the disease
down into a number of categories shown in Picture2 .
In the diagram in slide 2
are my conceptions of the major distinctions between the three major categories
of FSGS. There is a perihilar predominance of sclerosis in one variant of FSGS,
a glomerular tip location for a distinctive injury in the tip lesion variant of
FSGS, and a particular type of collapsing pattern of destruction of capillaries
and matrix expansion in the collapsing glomerulopathy variant of FSGS.
The diagram in Picture3 depicts
perihilar segmental sclerosis, which is continuous with the afferent arteriole
where the blood is coming into the glomerulus. A leading theory for the
pathogenesis of this variant is single nephron hypertension, hyperperfusion,
hyperfiltration. This is possibly analogous to a small local area of
arteriosclerosis (arteriolosclerosis) where plasma constituents are exuding
into the glomerular tuft much as plasma proteins exude into the walls of
arterioles causing the hyaline arteriolosclerosis of hypertension. The
PAS-stained section in Picture 4 shows the perihilar location of sclerosis with hyalinosis and lipids
vacuolation and an adhesion to Bowman's capsule. These are very distinctive and
characteristic features of focal segmental glomerulosclerosis, but they are not
specific. These features should be present in the absence of any other cause of
focal glomerular scarring in order to diagnose FSGS.
The electron micrograph in Picture5 shows
a relatively normal capillary wall to the left with effacement of foot
processes; and, to the right, a zone of sclerosis with some electron dense
material (that would corresponds to hyalinosis by light microscopy) and lipid
vacuolation.
Immunohistology
Picture 6
demonstrates entrapment of IgM and C3 in zones of sclerosis. Sometimes there
will be a small amount of IgM and C3 in the mesangium, as is sometimes the case
in normal individuals and patients with minimal change glomerulopathy.
Another feature of
perihilar FSGS that probably results from single nephron hypertension is
increased glomerular size (glomerular hypertrophy). Picture 7 compares an hypertrophied
glomerulus from an FSGS patient to a glomerulus from an age matched individual
who died secondary to trauma. By morphometric analysis, many but not all
specimens of FSGS have a mean glomerular size that is substantially larger the
normal range. This differs from minimal change glomerulopathy and glomerular
tip lesion, which suggests that tip lesion is pathogenetically different from
perihilar FSGS.
As with all other glomerular diseases, there are
primary and secondary variants of FSGS. The primary variants are just the ones
where we don't know what the underlying cause is (i.e., they probably should be
called idiopathic). The secondary variants of the perihilar focal segmental
glomerulosclerosis very often have glomerular enlargement (hypertrophy) and
very often have associated conditions that would cause overwork of the
glomeruli. For example, if you have normally sized kidneys but your body is
tremendously big, you are going to overwork the nephrons. Thus, the most common
cause for nephrosis in a morbidly obese patient is FSGS with big glomeruli. If
you have a normally sized body but you markedly reduce the amount of renal
parenchyma you have, you stress the available nephrons and develop secondary
focal segmental glomerulosclerosis. For example, FSGS can be secondary to
reflux nephropathy with pyelonephritis knocking out most of your functioning
parenchyma. The little bit that is left is stressed and develops FSGS. Also,
for reasons that are poorly understood, conditions of poor oxygenation will
lead to glomerular enlargement and predisposition to FSGS. For example, the
most common cause for nephrosis in sickle cell disease is FSGS.
The histologic lesion of the glomerular tip lesion
variant of FSGS affects the pole of the glomerulus adjacent to the origin of
the proximal tubule Picture 8. Other variants of FSGS, however, can involve the tip, but they have
lesions in other segments of glomeruli as well. Glomerular tip lesion has
histologic injury exclusively in the glomerular tip. For example, if there is
injury in the tip plus in the perihilar zone, it is not tip lesion. Early in
the disease, the glomerular tip lesion variant of FSGS often is more cellular
than sclerosing, and it often involves not only the visceral but also the
parietal epithelial cells at the origin of the proximal tubule and even some of
the most proximal tubular epithelial cells.
In the H&E stained
section in Picture9, the hilum is to the left. There are enlarged (hypertrophy), vacuolated
cells at the origin of the proximal tubule.
Picture 10 shows a PAS-stained section with the hilum to the left. There is a little
adhesion at the glomerular tip, and there is disturbance in matrix and cells at
the origin of the proximal tubule.
The trichrome stained section in Picture 11 shows
numerous foam cells, some increase in matrix, a tiny spot of hyalinosis and an
adhesion in the glomerular tip.
In the silver-stained
section in Picture 12, there is an arteriole to the left, and to the right there is an
epithelial response bulging into the origin of the proximal tubule with some
foam cells and a little bit of matrix disturbance. Glomerular tip lesion FSGS
seems to be different from the perihilar FSGS pathophysiologically because it
does not have glomerular enlargement and demographically it is very different
with respect to age and racial predilections. The greatest risk for developing
this pattern of FSGS is in older patients and whites rather than blacks, which
is the reverse of the age and racial predilection for other variants of FSGS.
The collapsing variant of FSGS has the greatest
predilection for blacks vs whites (approximately 80% of our collapsing
glomerulopathy FSGS patients are African-American). This collapsing
glomerulopathy variant of FSGS can be divided into primary (i.e., idiopathic)
variants and secondary variants. The secondary variants were recognized first
in association with intravenous drug abuse and HIV infection. Only later was
the occurrence of this pattern of glomerular injury observed in the absence of
drug abuse or HIV infection.
The collapsing variant of FSGS does not have a
predilection for any particular glomerular segments. Unlike tip lesion and
perihilar FSGS, which often have adhesion between Bowman's capsule and the
sclerotic segment, collapsing FSGS usually does not develop adhesions until the
sclerosis is very advanced. The epithelial cells adjacent to collapsed segments
are very hypertrophied(and sometimes hypertrophied) and often contain very
conspicuous hyaline droplets shown in the diagram in Picture 13.
These are resorption
droplets similar to but larger and more numerous than those seen in visceral
epithelial cells with any cause for nephrotic syndrome. Picture 14 shows a
silver-stained section with collapsing variant of FSGS. There is segmental
increase in matrix with obliteration of capillary lumens. Capillary loops have
collapsed into the increased matrix. There are hypertrophied, somewhat
hyperplastic, epithelial cells with conspicuous resorption droplets. The
epithelial hypertrophy and hyperplasia in some of these cases could be called
crescent formation; however, the convention has been that this kind of visceral
(rather than parietal) epithelial response in collapsing FSGS is not called
crescent formation.
Often the collapsing
glomerulopathy variant of FSGS is a more focal global process than a focal
segmental process, especially in patients with HIV nephropathy, who tend to
have more severe disease. Picture 15 shows a glomerulus from a patient with HIV nephropathy. Note the absence
of capillary loops, the collapse of matrix with no adhesions (even though there
is global sclerosis), and very conspicuous hypertrophied epithelial cells.
Especially with HIV
nephropathy, as shown in the trichrome stained section in Picture 16, there is
microscystic dilation of tubules. In fact, in most cases of collapsing FSGS,
there is substantial disturbance in the tubulointerstitial compartment. This
raises the possibility that collapsing FSGS actually affects not only
glomerular epithelial cells but also tubular epithelial cells.
In a patient with
collapsing FSGS, the electron microscopic marker that indicates HIV nephropathy
is the presence in the endothelial cells of tubuloreticular inclusions Picture17. These
tubuloreticular inclusions (TRI) appear to arise as a result of high levels of
alpha interferon in the circulation. The three settings in which
tubuloreticular inclusions are frequent are 1) HIV associated nephropathy, 2)
lupus nephritis, and 3) patients treated with alpha interferon (e.g. hepatitis
C patients). Anybody with HIV infection has TRI whether or not they have
nephrosis. Likewise, patients with lupus erythematosus have TRI whether or not
they have glomerulonephritis. Over 90% of patients with HIV nephropathy have
TRI, and lots of them. Around 80% of lupus nephritis patients have TRI. Less
than 5% of everybody else has TRI.
Collapsing FSGS has an
extreme black predilection, even when other risk factors are controlled. The
collapsing variant of FSGS has a very poor prognosis. After two years of
follow-up, about half the patients with idiopathic collapsing FSGS reach
end-stage renal disease. HIV associated collapsing glomerulopathy does even
worse. Therefore, collapsing FSGS is a very fulminate disease compared to the
perihilar and glomerular tip lesion variants of FSGS, which are relatively
indolent.
MEMBRANOUS GLOMERULOPATHY Nephrotic syndrome remits spontaneously and
completely in up to 40% of patients with membranous glomerulopathy. The natural
history of another 30 to 40% is characterized by repeated relapses and
remissions. The final 10 to 20% suffer a slow progressive decline in GFR that
typically culminates in ESRD after 10 to 15 years. Presenting features that
predict a poor prognosis include male gender, older age, hypertension, severe
proteinuria and hyperlipidemia, and impaired renal function. Controlled trials
of glucocorticoids have failed to show consistent improvement in proteinuria or
renal protection. This lesion is a leading cause of idiopathic nephrotic
syndrome in adults (30 to 40%) and a rare cause in children (<5%). It has a
peak incidence between the ages of 30 to 50 years and a male-female ratio of
2:1 (Table 3). Membranous glomerulopathy derives its name from the
characteristic light-microscopic appearance on renal biopsy, namely diffuse
thickening of the GBM, which is most apparent upon staining with periodic
acid-Schiff (PAS). Most patients (>80%) present with nephrotic syndrome,
proteinuria usually being nonselective. Microscopic hematuria is present in up
to 50% of cases, but red blood cells casts, macroscopic hematuria, and
leukocytes are extremely rare. Hypertension is documented in only 10 to 30% of
patients at the outset but is common later in patients with progressive renal
failure. Serologic tests such as antinuclear antibody, ANCA, anti-GBM antibody,
cryoglobulin titers, and complement levels are normal in the idiopathic form.
Light microscopy of renal biopsy sections reveals diffuse thickening of
the GBM without evidence of inflammation or cellular proliferation. Silver
staining demonstrates characteristic spikes along the GBM, which represent
projections of new basement membrane engulfing subepithelial immune deposits.
Immunofluorescence reveals granular deposition of IgG, C3, and the terminal
components of complement (C5b-9) along the glomerular capillary wall.
Electron-microscopic appearances vary depending on the stage of disease. The
earliest finding is the presence of subepithelial immune deposits. As these
deposits enlarge, spikes of new basement membrane extend out between the immune
deposits and begin to engulf them. With time, the deposits are completely
surrounded and incorporated into the basement membrane.
Membranous glomerulopathy is the most common cause for the nephrotic
syndrome in adults, whereas, minimal change glomerulopathy is the most common
cause for the nephrotic syndrome in children. Even though membranous
glomerulopathy is the most common cause in adults, it only accounts for about
1/3 of adults with nephrotic syndrome in my renal biopsy population. The
frequency of membranous glomerulopathy in other series ranges from around 20%
to around 50%, and most series are under 50%. Thus, in an adult with the
nephrotic syndrome, if you guess membranous glomerulopathy every time, you are
going to be wrong about 2/3 of the time. Therefore, in adults with nephrosis,
most nephrologists will biopsy to identify the underlying disease.
Picture
18 shows an H&E stained section of an early
stage. If you don't have a good internal reference as to the thickness of
capillary loops, it is hard to look at a membranous glomerulopathy biopsy and
be sure there is something wrong by light microscopy, especially during early
stages to the disease.
Picture19 shows a late stage membranous glomerulopathy with markedly thickened
capillary walls.
Looking at higher
magnification in the split-screen projection in Picture 20, the very thick capillary wall
of an overt case of membranous glomerulopathy can be recognized. On a trichrome
stained section (middle panel), if you have a good stain and if the stage of
the disease is just right and there are big deposits, you can see the
subepithelial immune complex deposits as fuchsinophilic (red) granular
deposits. The blue basement membrane is beneath the deposits and there are
projections of blue between them. On a silver stained section, and sometimes on
a well- stained PAS stained section, as shown in the panel on the right, you
can see the so-called spikes of basement membrane that project between the
deposits in certain stages of membranous glomerulopathy, in particular stage
II.
Picture21 is a diagram of the ultrastructural features of membranous glomerulopathy
(stage II) compared to a normal glomerulus. The characteristic lesion of
membranous glomerulopathy is deposition of immune complexes in the
subepithelial zone. In later stages of the disease, the deposits are
transformed into intramembranous deposits. Picture 21 diagrams a stage II lesion
with regularly distributed deposits with projections of basement membrane
between them. There also is effacement of foot processes in microvillous
transformation.
The electron micrograph Picture 22 of a stage II
membranous lesion demonstrates: capillary lumen, endothelial cytoplasm,
original basement membrane, subepithelial deposits (with actin condensation in
the overlying epithelium), and projections of basement membrane material
between the deposits.
Picture 23 diagrams the different stages of membranous glomerulopathy. In stage I
there are no basement membrane projections adjacent to deposits. In stage II
there are GBM projections between deposits. In stage III, the deposits become
incorporated in the basement membrane. In stage IV, the deposits start to fade
away leaving lucent gaps and a thickened basement membrane. The stage V lesion,
paradoxically, has a normal subepithelial zone of the basement membrane, which
has been repaired, and the disturbance has been pushed to the subendothelial
zone.
Picture 23 demonstrates the typical immunofluorescence microscopy pattern of
membranous glomerulopathy, in a panel adjacent to a low magnification electron
micrograph. The grains seen by immunofluorescence microscopy correspond to the
electron dense deposits. Typically, the granular staining of membranous
glomerulopathy is diffuse and global Picture24. Diffuse means all of the
glomeruli are involved, as opposed to focal, which means that some glomeruli
are involved and some are not. Global means that all the glomerular segments
and capillaries are involved in a given glomerulus, as opposed to segmental,
which means that only some of them are. Typically, membranous glomerulopathy
has diffuse global granular staining of capillary walls. Rare specimens will
have segmental staining. The composition of immune deposits is almost always
IgG-dominant. Usually there is some IgM and IgA. C3 staining is usually very
low intensity in idiopathic(primary) membranous glomerulopathy, which is very
different from a post-infectious glomerulonephritis in which there is usually
intense C3 staining along with very low intensity or absent IgG staining.
The pathogenesis of
membranous glomerulopathy is still not fully known. Current theory holds that a
likely pathogenesis for idiopathic or primary membranous glomerulopathy
involves an autoimmune disease in which circulating autoantibodies with
specificity for determinants on visceral epithelial cells develop. The
autoantibodies cross the glomerular basement membrane and form immune complexes
in-situ in the subepithelial zone. If this is the mechanism for forming the
subepithelial deposits, there could never be mesangial or subendothelial
deposits because the antigen is on the epithelial cell and ultrafiltration is
moving away from the lumen. However, if the membranous glomerulopathy is caused
by (secondary to) immune complexes that are composed of antigens from the
circulation (such as a hepatitis B antigen) and antibodies from the circulation,
some of the antibodies would bind to antigen that had crossed into the
subepithelial zone while other antibodies would form complexes in
subendothelial or mesangial locations This is the theoretical basis for
secondary membranous glomerulopathy, such as that caused by a neoplasm, an
infection or a systemic autoimmune disease. The presence of mesangial or
subendothelial dense deposits, therefore, raises the possibility of some type
of secondary membranous glomerulopathy.
MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS
There is no effective therapy for this disease.
Membranoproliferative glomerulonephritis (MPGN) can
present with the nephrotic syndrome, nephritic syndrome, or, most often, a
mixture of the two.
The two most common variants of MPGN are type I MPGN
(also called mesangiocapillary glomerulonephritis) and type II MPGN (also
called dense deposit disease). Type I is much more common than type II, which
is a rare disease.
The H&E stained section in Picture 26 shows the
characteristic histologic features of type I MPGN (and most cases of type II
MPGN). There is thickening of capillary walls. This is usually global and
diffuse but is occasionally at least focally and segmentally variable. There is
also hypercellularity. Much of this hypercellularity is mesangial
proliferation, and some of the capillary wall thickening is caused by mesangial
interposition into the subendothelial zone of the capillary loops. This is the
basis for the term mesangiocapillary glomerulonephritis.
Picture 27 shows the appearance of type I MPGN with PAS and trichrome stains.
Typically, there is doubling or complex replication of the basement membrane.
This is shown in this PAS- stained panel. This differs from the uniform narrow
linear staining of normal glomerular basement membranes. A trichrome stain
reveals thickening of capillary walls and mesangial matrix expansion, but it
usually does not demonstrate the basement membranes well enough to see the
replication.
The higher magnification silver stain in Picture 28 demonstrates
the so-called railroad track or tram track appearance of the replicated
basement membrane. The hypercellularity and capillary wall thickening may cause
hypersegmentation. The old name for this category of glomerulonephritis was
lobular glomerulonephritis because of this hypersegmentation. It is really not
an increase in segmentation at all. The segmentation is always there. Normally,
however, there is so much lucency from the capillary lumens that the
segmentation is not apparent.
The sine qua non of type I
MPGN is at the ultrastructural level and is the basis for the thickening in the
capillary walls. Electron microscopy demonstrates the difference between type I
and type II MPGN. The basis for the thickening in type I MPGN (mesangiocapillary
glomerulonephritis) is circumferential interposition of mesangial cytoplasm
into the peripheral capillary loop Picture
The electron micrograph in Picture 30 illustrates
features of type I MPGN. Moving from urinary space to capillary limen there is
the urinary space, effaced foot processes, the lamina lucida externa, lamina
densa, the subendothelial electron dense deposits which are lying adjacent to
the little fingers of mesangial cytoplasm that have extended into the
subendothelial zone, new basement membrane material, and endothelial cell with pores.
Most of the time, however,
the ultrastructure looks like Picture 31 with a very confused appearance. This electron micrograph shows the
urinary space, the effaced foot processes, the original basement membrane, and conspicuous
subendothelial deposits.
Immunofluorescence
microscopy Picture32 typically demonstrates peripheral granular or band-like staining that
may outline the hypersegmentation. In many patients with type I MPGN, C3 will
be the most conspicuous component in the deposits, especially in the idiopathic
childhood variant. Patients with MPGN often have hypocomplementemia and a
circulating autoantibody called C3 nephritic factor, which binds to the C3
convertase of the alternative pathway. Type I MPGN may be secondary to an
identifiable process, for example, a neoplasm or infection.
Hepatitis C infection is a
common cause for type I membranoproliferative glomerulonephritis, especially if
it is accompanied by mixed cryoglobulinemia. When mixed cryoglobulinemia is
present, sometimes as shown in picture33, there will be globular accumulations of cryoglobulin in the capillary
lumens. These can be seen by light microscopy as hyaline thrombi.
Sometimes, when the immune
complexes are derived from cryoglobulins, there will be tubular arrays in the
deposits that have about a 30-40 nanometer diameter. When these immunotactoids
are present in the absence of cryoglobulinemia, the appropriate diagnostic term
is immunotactoid glomerulopathy Picture. 34
This is an uncommon
disease that is sometimes accompanied by a B-cell neoplasms. Immunotactoid
glomerulopathy should not be confused with the more common disease called
fibrillary glomerulonephritis, which is characterized ultrastructurally by
approximately 20 nm diameter fibrils Picture35.
Type II Membranoproliferative Glomerulonephritis, (Dense Deposit Disease)
Type II membranoproliferative glomerulonephritis (dense deposit disease)
is a rare disease. Picture36 compares the H&E histology of type II MPGN
to a normal glomerulus. As with type I MPGN, in this specimen there is
hypercellularity and thickening of capillary walls.
Some patients with this rare
disease have thick capillary walls but no hypercellularity. In that setting,
descriptively, membranoproliferative glomerulonephritis isn't very appropriate,
which is why some nephropathologists prefer the term dense deposit disease
(DDD). The PAS(on left) and H&E-stained sections in Picture37 demonstrates
thickening of the basement membrane and capillary wall, respectively.
The diagram in Picture38 illustrates
the dense transformation of the basement membrane that causes the thickening.
The electron micrograph in
Picture 39 shows
the urinary space, an expanded mesangial region with a little bit of dense
material in the increased matrix, and capillary basement membrane with
stretches of normal lamina densa and zones of dense transformation.
Picture40 shows GBM as well as mesangial deposits. These dense deposits are not subepithelial
or subendothelial, but rather are within the basement membrane.
By immunofluorescence
microscopy Picture 41 there is intense staining for C3, typically with almost no staining for
immunoglobulin. The capillary wall staining is usually linear or bilinear.
There often are spherical or ring-shaped mesangial deposits that correspond to
the mesangial dense deposits observed by electron microscopy.
Type II MPGN has a higher
frequency of hypocomplementemia and C3 nephritic factor than type I MPGN.
In summary, a pathologic
diagnosis of MPGN requires not merely light microscopic recognition of an
appropriate pattern of glomerular injury, but, more importantly, specific
ultrastructural changes that are the diagnostic features of these diseases. Many
types of glomerular disease can produce light microscopic patterns of
glomerular injury that mimic MPGN, but the diagnostic term MPGN should be
reserved for the specific types of disease just described, and should be
further qualified as MPGN type I, MPGN type II or MPGN type III. Otherwise, a
diagnosis of MPGN would be of no value for predicting prognosis, identifying
possible causes and directing therapy.
FIBRILLARY-IMMUNOTACTOID
GLOMERULOPATHY. There is no proven therapy for fibrillary-immunotactoid glomerulopathy,
and many patients progress to ESRD over 1 to 10 years. Transplantation appears
to be a viable option in the latter setting.
MESANGIAL
PROLIFERATIVE GLOMERULONEPHRITIS. In general, persistent
nephrotic-range proteinuria signals a poor prognosis, with many patients
progressing to ESRD over 10 to 20 years despite immunosuppressive therapy.
Glucocorticoids and cyclophosphamide are the mainstays of treatment and
dramatically ameliorate glomerular injury. Steroids are usually administered
initially by pulse intravenous therapy on three consecutive days, followed by a
daily oral dose of about 1 mg/kg body weight tapered to zero over 3 to 6
months. Cyclophosphamide is typically administered orally at a daily dose of 1
to 2 mg/kg or as monthly intravenous pulses of 1 g/m2 of body surface area.
Plasmapheresis may be a useful adjunct in patients with severe nephritis
requiring dialysis. As many as 30% of patients relapse after treatment-induced
remission. A persistently elevated or rising ANCA titer may predict relapse in
individual patients; however, this relationship is not strong enough to justify
treatment based on titers alone. Recent studies demonstrate that administration
of trimethoprim-sulfamethoxazole reduces the relapse rate, possibly by eradicating
nasal carriage of Staphylococcus aureus. Dialysis and renal transplantation
afford excellent survival in patients with ESRD. Recurrence of Wegener's
granulomatosis in the allograft is rare. ACE inhibitors may help to slow the
progression to end-stage renal failure.
MINIMAL
CHANGE DISEASE. Alkylating agents are reserved for the small
number of patients who fail to achieve lasting remission. These include
patients who relapse during or shortly after withdrawal of steroids
(steroid-dependent) and those who relapse more than three times per year
(frequently relapsing). In these settings, cyclophosphamide (2 to 3 mg/kg per
day) or chlorambucil (0.1 to 0.2 mg/kg per day) is started after
steroid-induced remission and continued for 8 to 12 weeks. Cytotoxic agents may
also induce remission in occasional steroid-resistant cases. These benefits
must be balanced against the risk of infertility, cystitis, alopecia,
infection, and secondary malignancies, particularly in children and young
adults. Azathioprine has not been proven to be a useful adjunct to steroid
therapy. Cyclosporine induces remission in 60 to 80% of patients; it is an
alternative to cytotoxic agents and an option in patients who are resistant to
cytotoxic agents. Unfortunately, relapse is usual when cyclosporine is
withdrawn, and long-term therapy carries the risk of nephrotoxicity and other
side effects. Long-term renal and patient survival is excellent in MCD.
The etiology of MCD is unknown and the vast
majority of cases are idiopathic. MCD occasionally develops after upper
respiratory tract infection, immunizations, and atopic attacks. Patients with
atopy and MCD have an increased incidence of HLA-B12, suggesting a genetic
predisposition. MCD, often in association with interstitial nephritis, is a rare
side effect of nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, and
interferon-a. The occasional association with lymphoproliferative malignancies
(such as Hodgkin's lymphoma), the tendency for idiopathic MCD to remit during
intercurrent viral infection such as measles, and the good response of
idiopathic forms to immunosuppressive agents (see below) suggest an immune
etiology. In children, the urine contains albumin principally and minimal
amounts of higher molecular weight proteins such as IgG and a2-macroglobulin.
This selective proteinuria in conjunction with foot process effacement suggests
injury to podocytes and loss of the fixed negative charge in the glomerular
filtration barrier for protein. Proteinuria is typically nonselective in adults,
suggesting more extensive perturbation of membrane permeability.
There are many synonyms for minimal change
glomerulopathy, e.g., minimal change disease, lipoid nephrosis, nill disease.
The histologic section of an H&E stained glomerulus in shows the characteristic
light microscopic finding, i.e., no abnormality. Sometimes there may be a
little bit of mesangial hypercellularity in a few segments. Otherwise, any
scarring, any infiltration of leukocytes, any necrosis, or any other
substantial structural changes in glomeruli rule out a diagnosis of minimal
change glomerulopathy.
is a representative immunofluorescence micrograph of the immunohistology
of minimal change glomerulopathy, i.e., background staining. There are
occasional specimens that will have small amounts of exclusively mesangial
immunoglobulin (especially IgM) or complement accumulation that can still be
designated minimal change glomerulopathy. A little bit of mesangial IgM and/or
C3 without ultrastructural evidence for electron dense deposits is tolerable
for a diagnosis of minimal change glomerulopathy. When groups of patients with
absolutely no immunofluorescence findings have been compared to those that have
low levels of IgM dominant mesangial deposits without electron dense deposits,
they act no differently with respect to their clinical response to steroids and
long term outcomes. Well defined mesangial electron dense deposits, however,
worsen the prognosis for response to steroids or spontaneous remission. Thus,
if there are electron dense deposits, minimal change glomerulopathy is not an
appropriate diagnoses.
The
ultrastructural finding diagramed in are effacement of visceral epithelial foot
processes and epithelial microvillous transformation. Microvillous transformation
of epithelial cytoplasm often accompanies effacement. The effacement of foot
processes and microvillous transformation are not specific for minimal change
glomerulopathy. Foot process effacement is characteristic for minimal change
glomerulopathy and is required for the pathologic diagnosis of this disease;
however, this same change is present in any patient with substantial
proteinuria of any cause. Therefore, the diagnosis of minimal change
glomerulopathy is one of exclusion, i.e., these ultrastructural changes should
be present in the absence of light microscopic, immunohistologic or other
ultrastructural features of any other cause of proteinuria.
The electron
micrograph in is from a patient with minimal change glomerulopathy and shows almost
complete effacement of the visceral epithelial foot processes. There is
condensation of the epithelial cytoskeleton near the basement membrane. If you
don't know what this is, you can mistake it for subepithelial electron dense
deposits, suggesting membranous glomerulopathy. It is actin condensation that
takes place inside of visceral epithelial cytoplasm when there is effacement of
foot processes, suggesting that there is movement of cytoplasmic structures
during the effacement event.
TREATMENT
MCD is highly steroid-responsive and carries an
excellent prognosis. Spontaneous remission occurs in 30 to 40% of childhood
cases but is less common in adults. Approximately 90% of children and 50% of
adults enter remission following 8 weeks of high-dose oral glucocorticoids. In
a typical regimen using prednisone, children receive 60 mg/m2 of body surface
area daily for 4 weeks, followed by 40 mg/m2 on alternate days for an
additional 4 weeks; adults receive 1 to 1.5 mg/kg body weight per day for 4
weeks, followed by 1 mg/kg per day on alternate days for 4 weeks. Up to 90% of
adults enter remission if therapy is extended for 20 to 24 weeks. Nephrotic
syndrome relapses in over 50% of cases following withdrawal of glucocorticoids.
Alkylating agents are reserved for the small number of patients who fail to
achieve lasting remission. These include patients who relapse during or shortly
after withdrawal of steroids (steroid-dependent) and those who relapse more
than three times per year (frequently relapsing). In these settings,
cyclophosphamide (2 to 3 mg/kg per day) or chlorambucil (0.1 to 0.2 mg/kg per
day) is started after steroid-induced remission and continued for 8 to 12
weeks. Cytotoxic agents may also induce remission in occasional
steroid-resistant cases. These benefits must be balanced against the risk of
infertility, cystitis, alopecia, infection, and secondary malignancies,
particularly in children and young adults. Azathioprine has not been proven to
be a useful adjunct to steroid therapy. Cyclosporine induces remission in 60 to
80% of patients; it is an alternative to cytotoxic agents and an option in
patients who are resistant to cytotoxic agents. Unfortunately, relapse is usual
when cyclosporine is withdrawn, and long-term therapy carries the risk of
nephrotoxicity and other side effects. Long-term renal and patient survival is
excellent in MCD.
FOCAL
AND SEGMENTAL GLOMERULOSCLEROSIS WITH HYALINOSIS
Cyclophosphamide and
cyclosporine, when used at doses described above for MCD, induce partial or
complete remission in 50 to 60% of steroid-responsive patients but are
generally ineffective in steroid-resistant cases. Poor prognostic factors at
presentation include hypertension, abnormal renal function, black race, and
persistent heavy proteinuria. Renal transplantation is complicated by
recurrence of FSGS in the allograft in about 50% of cases and graft loss in
about 10%. Factors associated with an increased risk of recurrence include a
short time interval between the onset of the FSGS and ESRD, young age at onset,
and possibly the presence of mesangial hypercellularity on renal biopsy.
MEMBRANOUS
GLOMERULOPATHY. Cyclophosphamide, chlorambucil, and cyclosporine have each been shown
to reduce proteinuria and/or slow the decline in GFR in patients with progressive
disease in small or uncontrolled studies. These observations need to be
confirmed in controlled prospective studies. Transplantation is a successful
treatment option for patients who reach ESRD.
MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS
There is no effective therapy
for this disease.
FIBRILLARY-IMMUNOTACTOID
GLOMERULOPATHY. There is no proven therapy for fibrillary-immunotactoid
glomerulopathy, and many patients progress to ESRD over 1 to 10 years.
Transplantation appears to be a viable option in the latter setting.
MESANGIAL
PROLIFERATIVE GLOMERULONEPHRITIS. In general, persistent nephrotic-range
proteinuria signals a poor prognosis, with many patients progressing to ESRD
over 10 to 20 years despite immunosuppressive therapy.
POLYARTERITIS
NODOSA AND MICROSCOPIC POLYANGIITIS. Extreme-ly favorable
therapeutic results have been reported in classic PAN with the combination of
prednisone, 1 mg/kg per day, and cyclophosphamide, 2 mg/kg per. This regimen
has been reported to result in up to a 90% long-term remission rate even
following the discontinuation of therapy. In less severe cases of classic PAN,
glucocorticoids alone have resulted in disease remission. In addition,
long-term remissions have been reported in PAN associated with hepatitis B
virus anti-genemia using the antiviral agent vidarabine in combination with
plasma exchange with and without glucocorticoids. Favorable results have also
been reported in the treatment of PAN related to hepatitis B virus with IFN-a
and plasma exchange. Careful attention to the treatment of hypertension can
lessen the acute and late morbidity and mortality associated with renal,
cardiac, and central nervous system complications
of PAN. The treatment regimen for microscopic polyangiitis is similar to that
for Wegener's granulomatosis, particularly if glomerulonephritis is present.
Wegener's granulomatosis was
formerly universally fatal, usually within a few months after the onset of
clinically apparent renal disease. Glucocorticoids alone led to some
symptomatic improvement, with little effect on the ultimate course of the
disease. It has been well established that the most effective therapy in this
disease is cyclophosphamide given in doses of 2 mg/kg per day orally together
with glucocorticoids. The leukocyte count should be monitored closely during
therapy, and the dosage of cyclophosphamide should be adjusted in order to
maintain the count above 3000/uL, which generally maintains the neutrophil
count at approximately 1500/uL. With this approach, clinical remission can usually
be induced and maintained without causing severe leukopenia with its associated
risk of infection. Cyclophosphamide should be continued for 1 year following
the induction of complete remission and gradually tapered and discontinued
thereafter.
At the initiation of therapy,
glucocorticoids should be administered together with cyclophosphamide. This can
be given as prednisone, 1 mg/kg per day initially (for the first month of
therapy) as a daily regimen, with gradual conversion to an alternate-day schedule
followed by tapering and discontinuation after approximately 6 months.
Using the above regimen, the
prognosis of this disease is excellent; marked improvement is seen in more than
90% of patients, and complete remissions are achieved in 75% of patients. A
number of patients who developed irreversible renal failure but who achieved
subsequent remission on appropriate therapy have undergone successful renal
transplantation.
Despite the dramatic
remissions induced by the therapeutic regimen described above, long-term
follow-up of patients has revealed that approximately 50% of remissions are
later associated with one or more relapses. Reinduction of remission is almost
always achieved; however, a high percentage of patients ultimately have some
degree of morbidity from irreversible features of their disease, such as
varying degrees of renal insufficiency, hearing loss, tracheal stenosis, saddle
nose deformity, and chronically impaired sinus function. In evaluating patients
for relapse, the ANCA titer can be misleading. Many patients who achieve
remission continue to have elevated titers for years. In addition, over 40% of
patients who were in remission and had a fourfold increase in c-ANCA titer did
not have a relapse in disease. In this regard, therapy should not be
reinstituted or increased on the basis of a rise in the ANCA titer alone;
however, such a finding should prompt the clinician to examine the patient
carefully for any objective evidence of active disease and to monitor that
patient more closely.
Certain types of morbidity are related to toxic
side effects of treatment. Since the preceding therapeutic regimen calls for
conversion to alternate-day glucocorticoid therapy within 3 months and ultimate
discontinuation within 6 to 12 months, glucocorticoid-related side effects such
as diabetes mellitus, cataracts, life-threatening infectious disease
complications, serious osteoporosis, and severe cushingoid features are
infrequently encountered except in those patients requiring prolonged courses
of daily glucocorticoids. However, cyclophosphamide-related toxicities are more
frequent and severe. Cystitis to varying degrees occurs in 50% of patients,
bladder cancer in 6%, and myelodysplasia in 2%.
Some reports have indicated therapeutic success with
less frequent and severe toxic side effects using intermittent boluses of
intravenous cyclophosphamide (l g/m2 per month) in place of daily drug
administered orally. However, we and others have found an increased rate of
relapse with bolus intravenous cyclophosphamide. We therefore strongly
recommend that the drug be given as daily oral therapy
2.3, 2.4.
Glucocorticoids. Immunosuppressive therapy. (continue)
Despite concerns regarding toxicity, a regimen of daily cyclophosphamide
and glucocorticoids is clearly the treatment of choice in patients with
immediately life-threatening disease such as rapidly progressive
glomerulonephritis. However, methotrexate together with glucocorticoids may be
considered as an alternative for initial therapy for certain patients whose
disease is not immediately life-threatening or as a switch regimen in those
patients who have experienced significant cyclophosphamide toxicity. In one
study, patients in this category were given oral prednisone as described above,
and methotrexate was administered orally starting at a dosage of 0.3 mg/kg,
with a maximum of 15 mg/week. If the treatment was well tolerated after 1 to 2
weeks, the dosage was increased by 2.5 mg weekly up to a dosage of 20 to 25
mg/week and maintained at that level. Remissions were achieved in 33 of 42
patients (79%). Nineteen patients relapsed; 15 of these 19 relapses occurred
when patients were receiving 15 mg or less of methotrexate per week; 13 of
these 19 were treated with a second course of methotrexate and prednisone and
10 of 13 achieved a second remission. Toxicities of methotrexate included
elevated transaminase levels (24%), leukopenia (7%), opportunistic infection
(9.5%), methotrexate pneumonitis (7%), and stomatitis (2%).
Azathioprine, in doses of 1 to 2 mg/kg per day, has proven effective in
some patients, particularly in maintaining remission in those in whom remission
was induced by cyclophosphamide. The drug should be administered together with
the glucocorticoid regimen described above. Although certain reports have
indicated that trimethoprim-sulfamethoxazole may be of benefit in the treatment
of Wegener's granulomatosis, there are no firm data to substantiate this,
particularly in patients with serious renal and pulmonary disease. In a study
examining the effect of trimethoprim-sulfamethoxazole on relapse, decreased
relapses were shown only with regard to upper airway disease, and no
differences in major organ relapses were observed.
Trimethoprim-sulfamethoxazole alone should never be used to treat active
Wegener's granulomatosis outside of the upper airway.
2.5. Heparinotherapy.
Anticoagulation is indicated for patients with
deep venous thrombosis, arterial thrombosis, and pulmonary embolism. Patients
may be relatively resistant to heparin as a consequence of antithrombin III
deficiency. Renal vein and vena caval angiography are probably indicated only
when embolization occurs on anticoagulation and insertion of a caval filter is
contemplated.
Patients with serum albumin less than 2 g/dl can
become hypercoagulable. Nephrotic patients have urinary losses of antithrombin
III, protein C, and protein S and increased platelet activation. Patients are
prone to renl vein thrombosis and other venous thromboemboli. Anticoagulation
therapy is warranted for at least 3 – 6 months in patients with evidence of
thrombosis. Patients with renal vein thrombosis and recurrent thromboemboli
probably require lifetime anticoagulation.
2.6. Platelet
aggregation inhibitor.
Dipyridamole 200-400 mg/d, and Aspirin 0.25 g/d, 4-6 months, trental
300-1000 mg i/v 10-15 days. Then per os trental 300-600 mg/d 2-4 months.
2.7.
Aiotensin-converting enzyme (ACE) inhibitors.
Nonspecific measures that may reduce proteinuria include
angiotensin-converting enzyme (ACE) inhibitors, and NSAIDs. The first of these
measures aim to reduce proteinuria and slow the rate of progression of renal
failure by lowering intraglomerular pressure and preventing the development of
hemodynamically mediated focal segmental glomerulosclerosis. There is conclusive
evidence that ACE inhibitors are renoprotective in human diabetic nephropathy
and that ACE inhibitors slow the development of secondary FSGS in experimental
animals. Their role in the treatment of nephrotic syndrome in other settings is
unproven. NSAIDs also reduce proteinuria in some patients with nephrotic
syndrome, probably by altering glomerular hemodynamics and GBM permeability
characteristics. This potential benefit must be balanced against the risk of
inducing acute renal failure, hyperkalemia, salt and water retention, and other
side effects.
3. Treatment of the pyelonephritis.
The following principles underlie the treatment
of UTIs:
1. Except
in acute uncomplicated cystitis in women, a quantitative urine culture, a Gram
stain, or an alternative rapid diagnostic test should be performed to confirm
infection before treatment is begun. When culture results become available,
antimicrobial sensitivity testing should be used to direct therapy.
2. Factors
predisposing to infection, such as obstruction and calculi, should be
identified and corrected if possible.
3. Relief
of clinical symptoms does not always indicate bacteriologic cure.
4. Each
course of treatment should be classified after its completion as a failure
(symptoms and/or bacteriuria not eradicated during therapy or in the immediate
posttreatment culture) or a cure (resolution of symptoms and elimination of
bacteriuria). Recurrent infections should be classified as same-strain or
different-strain and as early (occurring within 2 weeks of the end of therapy)
or late.
5. In
general, uncomplicated infections confined to the lower urinary tract respond
to short courses of therapy, while upper tract infections require longer
treatment. After therapy, early recurrences due to the same strain may result
from an unresolved upper tract focus of infection but often (especially after
short-course therapy for cystitis) result from persistent vaginal colonization.
Recurrences >2 weeks after the cessation of therapy nearly always represent
reinfection with a new strain or with the previously infecting strain that has
persisted in the vaginal and rectal flora.
6. Despite
increasing resistance, community-acquired infections, especially initial
infections, are usually due to more antibiotic-sensitive strains.
7. In
patients with repeated infections, instrumentation, or recent hospitalization,
the presence of antibiotic-resistant strains should be suspected.
3.1 Antibiotics
and uroseptics
In women, acute uncomplicated pyelonephritis without accompanying clinical
evidence of calculi or urologic disease is due to E. coli in most cases.
Although the optimal route and duration of therapy have not been established, a
7- to 14-day course of a fluoroquinolone, an aminoglycoside, or a
third-generation cephalosporin is usually adequate. Neither ampicillin nor
TMP-SMZ should be used as initial therapy because >25% of strains of E. coli
causing pyelonephritis are now resistant to these drugs in vitro. For at least
the first few days of treatment, antibiotics should probably be given
intravenously to most patients, but patients with mild symptoms can be treated
for 7 to 14 days with an oral antibiotic (usually ciprofloxacin or ofloxacin),
with or without an initial single parenteral dose (Table 1). Patients who fail
to respond to treatment within 72 h or who relapse after therapy should be
evaluated for unrecognized suppurative foci, calculi, or urologic disease.
|
Table 1. Treatment Regimens for Bacterial Urinary
Tract Infections |
||||||
|
Condition |
Characteristic
Pathogens |
Mitigating
Circumstances |
Recommended
Empirical Treatmenta |
|||
|
Acute
un-complicated cystitis in women |
Escherichia coli, Staphy-lococcus
saprophyti-cus, Proteus mirabilis, Klebsiella pneumoniae |
None |
3-Day regimens: oral
trimethoprim-sulfamethoxazole, trimethoprim, quinolone; 7-day regimen:
macrocrystalline nitrofurantoinb |
|||
|
|
|
Diabetes,
symptoms for >7 d, recent urinary tract infection, use of
diaphragm, age >65 years |
Consider 7-day regimen:
oral trimethoprim-sulfamethoxazole, trimethoprim, quinoloneb |
|||
|
|
|
Pregnancy |
Consider 7-day
regimen: oral amoxicillin, macrocrystalline nitrofurantoin, cefpodoxime
proxetil, or trimethoprim-sulfamethoxazole b |
|||
|
Acute uncom-plicated
pye-lonephritis in women |
E. coli, P. mirabilis, S.
sapro-phyticus |
Mild to moderate
illness, no nausea or vomiting; outpatient therapy |
Oralc
quinolone for 7-14 d (initial dose given IV if desired); or single-dose
ceftriaxoned or gentami-cind IV followed
by oral trimethoprim-sulfamethoxazole b for 14 d |
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|
|
|
Severe illness or
possible urosepsis: hospitalization required |
Parenterald
ceftriaxone, quinolone, gentamicin (± ampicillin), or
aztreonam until defervescence; then oralc quinolone,
cephalosporin, or trimethoprim-sulfa-methoxazole for 14 d |
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|
Complicated
urinary tract infection in men and women |
E. coli, Proteus,
Klebsiella, Pseudomonas, Serratia, enterococci,
staphylococci |
Mild to moderate
illness, no nausea or vomiting: outpatient therapy |
Oralc
quinolone for 10-14 d |
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|
|
|
Severe illness or
possible urosepsis: hospitalization required |
Parenterald
ampicillin and gentamicin, quinolone, ceftriaxone, aztreonam, ticarcillin/clavulanate,
or imipenem-cilastatin until defervescence; then oralc
quinolone or trimethoprim-sulfame-thoxazole for 10-21 d |
|
||
|
a Treatments listed are those
to be prescribed before the etiologic agent is known; Gram's staining can be
helpful in the selection of empirical therapy. Such therapy can be modified
once the infecting agent has been identified. Fluoroquinolones should not be
used in pregnancy. trimethoprim-sulfamethoxazole, although not approved for
use in pregnancy, has been widely used. Gentamicin should be used with
caution in pregnancy because of its possible toxicity to eighth-nerve
development in the fetus. |
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|
b Multiday oral regimens for cystitis are as follows: trimethoprim-sulfamethoxazole, 160/800 mg q12h; trimethoprim, 100 mg q12h; norfloxacin, 400 mg q12h; ciprofloxacin, 250 mg q12h; ofloxacin, 200 mg q12h; lomefloxacin, 400 mg/d; enoxacin, 400 mg q12h; macrocrystalline nitrofurantoin, 100 mg qid; amoxicillin, 250 mg q8h; cefpodoxime proxetil, 100 mg q12h. |
||||||
|
c Oral regimens for
pyelonephritis and complicated urinary tract infection are as follows:
trimethoprim-sulfamethoxazole, 160/800 mg q12h; ciprofloxacin, 500 mg q12h;
ofloxacin, 200-300 mg q12h; lomefloxacin, 400 mg/d; enoxacin, 400 mg q12h;
amoxicillin, 500 mg q8h; cefpodoxime proxetil, 200 mg q12h. |
||||||
|
d Parenteral regimens are as
follows: ciprofloxacin, 200-400 mg q12h; ofloxacin, 200-400 mg q12h;
gentamicin, 1 mg/kg q8h; ceftriaxone, 1-2 g/d; ampicillin, |
||||||
Complicated UTIs (those arising in a setting of
catheterization, instrumentation, urologic anatomic or functional abnormalities,
stones, obstruction, immunosuppression, renal disease, or diabetes) are
typically due to hospital-acquired bacteria, including E. coli, Klebsiella,
Proteus, Serratia, Pseudomonas, enterococci, and staphylococci. Many of the
infecting strains are antibiotic-resistant. Empirical antibiotic therapy
ideally provides broad-spectrum coverage against these pathogens. In patients
with minimal or mild symptoms, oral therapy with a fluoroquinolone, such as
ciprofloxacin or ofloxacin, can be administered until culture results and
antibiotic sensitivities are known. In patients with more severe illness,
including acute pyelonephritis or suspected urosepsis, hospitalization and
parenteral therapy should be undertaken. Commonly used empirical regimens include
imipenem alone, a penicillin or cephalosporin plus an aminoglycoside, and (when
the involvement of enterococci is unlikely) ceftriaxone or ceftazidime. When
information on the antimicrobial sensitivity pattern of the infecting strain
becomes available, a more specific antimicrobial regimen can be selected.
Therapy should generally be administered for 10 to 21 days, with the exact
duration depending on the severity of the infection and the susceptibility of
the infecting strain. Follow-up cultures 2 to 4 weeks after cessation of
therapy should be performed to demonstrate cure.
3.2. NSAIDs.
Antibiotic therapy is combined with NSAIDs such as diclofenac (Like
nonsteroidal anti-inflammatory drugs, diclofenac inhibits the actions of
prostaglandins), meloxicam (meloxicam is a nonsteroidal anti-inflammatory drug
that exhibits anti-inflammatory, analgesic, and antipyretic activities in
animal models. The of action of meloxicam may be related to prostaglandin
synthetase (cyclooxygenase) inhibition), indomethacin (indomethacin inhibits
the activity of the enzyme cyclooxygenase to decrease the formation of
precursors of prostaglandins and thromboxanes from arachidonic acid).
3.3. Treatment of the local hemodynamic
disorders.
Restore the normal urine passage is one of the
main tests in the treatment patients with pyelonephritis. Hemodynamic disorder
furthers development of the chronic pyelonephritis. That is why drugs improving
microcirculation (euphyllin, dipyridamole, agapurin, pentoxifylline) venous ebb
from kidneys (venoruton), anti-inflammatory drugs (NSAIDs, aspirin, small doses
of heparin).
3.4. Corection of the
secondary immunologic insufficient.
Secondary immune insufficiency requires correction on the all phases of
treatment. There are used such drugs as methyluracilum, pentoxifylline,
dibasole, echinaceae.
3.5. Preventation of the
recurrence.
After liquidation acute inflammatory process preventional course of
trearment with antibiotics, herbal diuretics
Women who experience frequent symptomatic UTIs (>3 per year on
average) are candidates for long-term administration of low-dose antibiotics
directed at preventing recurrences. Such women should be advised to avoid
spermicide use and to void soon after intercourse. Daily or thrice-weekly
administration of a single dose of TMP-SMZ (80/400 mg), TMP alone (100 mg), or
nitrofurantoin (50 mg) has been particularly effective. Norfloxacin and other
fluoroquinolones have also been used for prophylaxis. Prophylaxis should be
initiated only after bacteriuria has been eradicated with a full-dose treatment
regimen. The same prophylactic regimens can be used after sexual intercourse to
prevent episodes of symptomatic infection in women in whom UTIs are temporally
related to intercourse. Other patients for whom prophylaxis appears to have
some merit include men with chronic prostatitis; patients undergoing
prostatectomy, both during the operation and in the postoperative period; and
pregnant women with asymptomatic bacteriuria. All pregnant women should be
screened for bacteriuria in the first trimester and should be treated if
bacteriuria is demonstrated.
3.6. Phytotherapy.
Decoction of the diuretics plants (hips, parsleys’ roots and others).
1.
2. Renal arterial hypertension.
Renal hypertension
A. Chronic
pyelonephritis
B. Acute and chronic
glomerulonephritis
C. Polycystic renal
disease
D. Renovascular stenosis
or renal infarction
E. Most other severe renal
diseases (arteriolar nephrosclerosis, diabetic nephropathy, etc.)
F. Renin-producing tumors
Renovascular Hypertension. Over the past decades the standard approach
to screen for renovascular hypertension has progressed from the rapid-sequence
IVP to one of three noninvasive techniques: the captopril-enhanced radionuclide
renal scan (the preferred choice), a duplex Doppler flow study, or magnetic
resonance (MRI) angiography. However, perhaps the most sensitive and specific
screening test, the spiral computed tomography (CT) scan, which gives a
three-dimensional view, unfortunately also requires giving an intravenous contrast
agent.
The definitive test for surgically correctable renal disease is the
combination of a renal angiogram and renal vein renin determinations. The renal
arteriogram both establishes the presence of a renal arterial lesion and aids
in the determination of whether the lesion is due to atherosclerosis or to one
of the fibrous or fibromuscular dysplasias.
It does not, however, prove that the lesion is responsible for the
hypertension, nor does it permit prediction of the chances of surgical cure. It
must be noted that (1) renal artery stenosis is a frequent finding by
angiography and at postmortem in normotensive individuals, and (2) essential
hypertension is a common condition and may occur in combination with renal
arterial stenosis that is not responsible for the hypertension. Bilateral renal
vein catheterization for measurement of plasma renin activity is therefore used
to assess the functional significance of any lesion noted on arteriography.
When one kidney is ischemic and the other is normal, all the renin released
comes from the involved kidney. In the most straightforward situation, the
ischemic kidney has a significantly higher venous plasma renin activity than
the normal kidney, by a factor of 1.5 or more. Moreover, the renal venous blood
draining the uninvolved kidney exhibits levels similar to those in the inferior
vena cava below the entrance of the renal veins.
Significant benefit from operative correction may be anticipated in at
least 80% of patients with the findings described above if care is taken to
prepare the patient properly before renal vein blood sampling, i.e., by
discontinuing renin-suppressing drugs, such as beta blockers, for at least 10
days; restricting the patient to a low-sodium intake for 4 days; and/or giving
a converting-enzyme inhibitor for 24 h. When obstructing lesions in the
branches of the renal arteries are demonstrated by arteriography, an attempt to
obtain blood samples from the main branches of the renal vein should be made in
an effort to identify a localized intrarenal arterial lesion responsible for
the hypertension.
Hypertension and Left
Ventricular Hypertrophy.
Hypertension is the most common complication of chronic renal disease
and end-stage renal disease. When it is not found, the patient may have a salt-wasting
form of renal disease (e.g., medullary cystic disease, chronic
tubulointerstitial disease, or papillary necrosis), may be receiving
antihypertensive therapy, or be volume-depleted, the last condition usually due
to excessive gastrointestinal fluid losses or overzealous diuretic therapy.
Since volume overload is the major cause of hypertension in uremia, the
normotensive state can often be restored by appropriate use of diuretics in the
predialysis patient or with aggressive ultrafiltration in dialysis patients.
Nevertheless, because of hyperreninemia, some patients remain hypertensive
despite rigorous salt and water restriction and ultrafiltration. Rarely,
patients develop accelerated or malignant hypertension. Intravenous
nitroprusside, labetolol, or more recently approved agents such as fenoldopam
or urapidil, together with control of ECFV, generally controls such
hypertension. Subsequently, such patients usually require more than one oral
antihypertensive drug. Enalaprilat or other ACE inhibitors may also be
considered, but in the face of bilateral renovascular disease they have the
potential to further reduce GFR abruptly. Administration of erythropoietin
(EPO) may raise blood pressure and increase the requirement for
antihypertensive drugs. A high percentage of patients with CRD present with
left ventricular hypertrophy or dilated cardiomyopathy. These are among the
most ominous risk factors for excess cardiovascular morbidity and mortality in
patients with CRD and ESRD and are thought to be related primarily to prolonged
hypertension and ECFV overload. In addition, anemia and the surgical placement
of an arteriovenous anastomosis for future or ongoing dialysis access may
generate a high cardiac output state, which also intensifies the burden placed
on the left ventricle.
Diagnosis
of the renal arterial hypertension.
Renovascular Hypertension. Over the past decades the standard approach
to screen for renovascular hypertension has progressed from the rapid-sequence
IVP to one of three noninvasive techniques: the captopril-enhanced radionuclide
renal scan (the preferred choice), a duplex Doppler flow study, or magnetic
resonance (MRI) angiography. However, perhaps the most sensitive and specific
screening test, the spiral computed tomography (CT) scan, which gives a
three-dimensional view, unfortunately also requires giving an intravenous
contrast agent.
The definitive test for surgically correctable
renal disease is the combination of a renal angiogram and renal vein renin
determinations. The renal arteriogram both establishes the presence of a renal
arterial lesion and aids in the determination of whether the lesion is due to
atherosclerosis or to one of the fibrous or fibromuscular dysplasias. It does
not, however, prove that the lesion is responsible for the hypertension, nor
does it permit prediction of the chances of surgical cure. It must be noted
that (1) renal artery stenosis is a frequent finding by angiography and at
postmortem in normotensive individuals, and (2) essential hypertension is a common
condition and may occur in combination with renal arterial stenosis that is not
responsible for the hypertension. Bilateral renal vein catheterization for
measurement of plasma renin activity is therefore used to assess the functional
significance of any lesion noted on arteriography. When one kidney is ischemic
and the other is normal, all the renin released comes from the involved kidney.
In the most straightforward situation, the ischemic kidney has a significantly
higher venous plasma renin activity than the normal kidney, by a factor of 1.5
or more. Moreover, the renal venous blood draining the uninvolved kidney
exhibits levels similar to those in the inferior vena cava below the entrance
of the renal veins.
Renal artery stenosis should be
suspected when hypertension develops in a previously normotensive individual
over 50 years of age or in the young (under 30 years) with suggestive features:
symptoms of vascular insufficiency to other organs, high-pitched epigastric
bruit on physical examination, symptoms of hypokalemia secondary to
hyperaldosteronism (muscle weakness, tetany, polyuria), and metabolic
alkalosis. If renal arterial stenosis is suspected, the best initial screening
test is a renal ultrasound, which may reveal unilateral renal hypotrophy (but
normal cortical echogenicity). Absence of compensatory hypertrophy in the
contralateral kidney should raise the suspicion of bilateral stensosis or
superimposed intrinsic (structural) renal disease, most commonly hypertensive
or diabetic nephropathy. A positive captopril test, which has a sensitivity and
specificity of greater than 95%, constitutes an excellent follow-up procedure
to assess the need for more invasive radiographic evaluation. The test relies
on the exaggerated increase in plasma renin activity (PRA) after administration
of captopril to patients with renovascular hypertension as compared with those
with essential hypertension. It is considered positive when all the following
criteria are satisfied: stimulated PRA of 12 (ug/L)/h, absolute increase in PRA
of 10 (ug/L)/h or more, and increase in PRA of >150% [or 400% if baseline
PRA is <3 (ug/L)/h]. Because ACE inhibitors magnify the impairment in renal
blood flow and glomerular filtration rate (GFR) caused by functionally significant
renal artery stenosis, use of these drugs in association with 99mTc-DTPA or
99mMAG3 renography greatly enhances the predictive value of radionuclide
renography (>90% sensitivity and specificity). Magnetic resonance
angiography (MRA) has replaced previous modalities as the most sensitive (100%)
and specific (95%) test for the diagnosis of renal arterial stenosis. The most
definitive diagnostic procedure is bilateral arteriography with repeated
bilateral renal vein and systemic renin determinations. If renal vein renin
measurements from the two kidneys differ by a factor of 1.5:1 or more (higher
value from the affected kidney) in a patient with radiographic unilateral renal
artery stenosis, the chance of cure of hypertension by surgical reconstruction
or angioplasty is almost 90%, particularly if the renal vein renin level from
the unaffected kidney is equal to or less than systemic levels (suppressible).
A ratio of less than 1.5:1, however, does not exclude the diagnosis of
renovascular hypertension, particularly in the presence of bilateral disease
References.
A
- Basic:
1.
Davidson’s Principles and practice of
medicine (21st revised ed.) / by Colledge N.R., Walker B.R., and
Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.
2.
3.
The Merck Manual of Diagnosis and
Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. –
published by Merck Research Laboratories, 2011.
4.
Web -sites:
a)
www.tdmu.edu.ua:
Management of patients with urinary syndrome
b)
http://emedicine.medscape.com/
c)
http://meded.ucsd.edu/clinicalmed/introduction.htm
B
– Additional:
1.
Eugene Braunwald, Anthony Fauci et
al: Harrison’s principles of internal medicine. McGraw-Hill. Medical Publishing
Division, 15th edition, 2000.
2.
Lawrence M. Tierney, Jr. et al: Current
Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health
Professions Division, 2000.
3.
Christopher R.W. Edwards et al:
Davidson’s principles and practice
of medicine, 17th edition,
Educational Low-Priced Books Scheme funded by the British Government, 1995