The exact mechanisms leading to the development of diabetic nephropathy are not
clearly defined; however, several predictive factors for the development and
progression of kidney damage have been identified. These include elevated BP,
plasma glucose, glycosylated hemoglobin, and cholesterol; smoking; advanced age;
male sex; and, potentially, high protein intake.
Insulin deficiency and increased
ketone bodies have also been proposed as contributors to the pathogenesis.
Advanced glycosylation end products (AGE) that form in conditions of
hyperglycemia have also been implicated as a cause of end-organ damage. The
accumulation of multiple AGE is associated with the severity of kidney disease in
patients with diabetic nephropathy.
76 A genetic predisposition exists in that higher
rates of diabetes and nephropathy, hypertension, cardiovascular events, albuminuria,
and elevated BP have been observed in relatives of patients with type 2 diabetes.
Certain genes and polymorphisms have also been associated with the development of
diabetic nephropathy, and further exploration into this area may prove beneficial in
identifying high-risk patients.
CASE 28-1, QUESTION 3: What is the significance of G.B.’s albuminuria?
Albuminuria, the earliest sign of kidney involvement in patients with diabetes
mellitus, correlates with the rate of progression of kidney disease. Albuminuria not
only indicates renal damage but is also a powerful predictor of cardiovascular
1 For most patients, eGFR begins to decline once proteinuria
is established. Because of this association, annual testing for the presence of
microalbuminuria is indicated in patients who have had type 1 diabetes for more than
5 years and in all patients with type 2 diabetes starting at diagnosis.
of albuminuria indicates irreversible kidney damage. G.B. has likely reached the
point at which such damage is inevitable because her urinary protein exceeds ranges
normally observed at the earlier stages of kidney disease. G.B.’s current laboratory
data suggest that she has substantial kidney disease and has developed associated
complications of the disease. Although progression to ESRD is generally beyond
prevention at this stage, appropriate intervention can slow the progression to ESRD
for G.B. Progressive diabetic nephropathy consists of proteinuria of varying severity
occasionally leading to nephrotic syndrome with hypoalbuminemia, edema, and an
increase in circulating LDL cholesterol as well as progressive azotemia.
CASE 28-1, QUESTION 4: How should G.B.’s kidney disease be managed?
Because reversal of G.B.’s kidney disease is not possible, the primary goals are to
delay the need for dialysis therapy as long as possible and to manage complications.
The three main risk factors for the progression of incipient nephropathy to clinical
diabetic nephropathy are poor glycemic control, systemic hypertension, and high
dietary protein intake (>1.3 g/kg/day). G.B.’s current random blood glucose
concentration of 289 mg/dL, history of elevated glucose on prior visits, and elevated
indicate poorly controlled diabetes, which will accelerate the
progression of diabetic nephropathy and time to ESRD. Thus, her blood glucose
concentrations should be maintained within target goals while avoiding
hypoglycemia. G.B.’s elevated BP is likely the result of kidney disease and changes
in intravascular volume; reduction in BP may prevent further damage to functioning
nephrons and slow the progression to ESRD. Similarly, reductions in dietary protein
intake (dietary protein intake of approximately 0.8 g/kg body weight/day) should be
initiated in an attempt to reduce the rate of further progression, although this needs to
be evaluated in the context of her overall nutritional status.
Strict glycemic control can improve diabetic management, reduce proteinuria, and
slow the rate of decline in eGFR. The Diabetes Control and Complications Trial
(DCCT), a randomized clinical trial of type 1 diabetic patients (n = 1,441),
demonstrated that maintaining fasting blood glucose concentrations between 70 and
120 mg/dL, with postprandial blood glucose concentrations less than 180 mg/dL,
delayed the onset and progression of microvascular diseases such as diabetic
nephropathy and reduced the risk of CKD. Patients were randomly assigned to
receive either conventional insulin treatment (one to two insulin doses a day) or
intensive treatment (three or more insulin doses a day). After a mean follow-up of 6.5
years, the intensive insulin regimen reduced the overall risk of moderately increased
albuminuria by 39% and severely increased albuminuria by 54%. Unfortunately,
stricter glycemic control was associated with an increased incidence of
The UK Prospective Diabetes Study (UKPDS) demonstrated the beneficial effects
of intensive glycemic control in patients with type 2 diabetes (n = 3,867). During a
10-year treatment period, intensive glucose control (fasting glucose <108 mg/dL)
with either insulin or an oral sulfonylurea reduced microvascular complications (e.g.,
retinopathy and nephropathy), including albuminuria by 33%, when compared with
conventional dietary therapy (fasting glucose <270 mg/dL). Similar to the DCCT,
intensive treatment groups in the UKPDS experienced more hypoglycemic
Additionally diabetes trials such as Action to Control Cardiovascular Risk in
Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and
Diamicron MR Controlled Evaluation (ADVANCE) evaluated the macrovascular
and microvascular outcomes associated with intensive glucose control in type 2
diabetics. The ACCORD trial showed a 21% reduction in the development of
moderately increased albuminuria cases and a 32% reduction in severely increased
In the ADVANCE trial, there was a 9% reduction in moderately
increased albuminuria and 30% reduction in progression to
severely increased albuminuria.
83 Similar to other studies, severe hypoglycemia,
although uncommon, was more common in the intensive-control group.
KDIGO Guidelines for Evaluation and Management of CKD recommend a
hemoglobin A1c of approximately 7% to prevent or delay progression of the
microvascular complications of diabetes including diabetic kidney disease. Targeting
less than 7% increases patients’ risk of experiencing hypoglycemia and
without improvements in cardiovascular outcomes and should be avoided. In CKD
patients with diabetes and comorbidities or a limited life expectancy and risk of
hypoglycemia, a target A1c above 7.0% is suggested.
G.B. will benefit from a multifactorial approach addressing glycemic control and
hypertension to slow her progression of CKD from DM. Appropriately dosed oral
and/or insulin therapy can achieve these goals despite her advanced kidney disease.
G.B. should be counseled on appropriate techniques for home glucose monitoring,
particularly given her history of noncompliance. Compliance with this regimen will
require motivation as well as encouragement from G.B.’s family and health care
providers. (See Chapter 53, Diabetes Mellitus, for a more complete discussion of
intensive insulin therapy and counseling.)
Systemic hypertension usually occurs with the development of normal to moderately
progression of kidney disease in both groups. The coexistence of these disorders
further increases the risk of cardiovascular events. Hypertension may be a result of
underlying diabetic nephropathy and increased plasma volume or increased
peripheral vascular resistance. Regardless of the etiology, virtually any level of
untreated hypertension (either systemic or intraglomerular) is associated with a
reduction in eGFR. As such, the control of systemic and intraglomerular BP is
perhaps the single most important factor for retarding the progression of kidney
disease and has been shown to increase life expectancy in patients with type 1
Patients with diabetes and hypertension exhibit elevated systemic vascular
resistance and increased vasoconstriction from angiotensin II, which are in large part
responsible for the glomerular damage characteristic of diabetic nephropathy.
Although the management of hypertension with virtually any agent can attenuate the
progression of kidney disease, ACEIs, which inhibit the synthesis of angiotensin II,
and ARB, which block angiotensin II AT 1
receptors, are preferred owing, in part, to
the effects of these agents on renal hemodynamics (Fig. 28-1). KDIGO guidelines
recommend ACEI or ARB for the treatment of hypertension in all CKD patients with
AER >300 mg/24 hour and diabetic CKD adults with AER ≥30 mg/24 hour.
recommends ACEI or ARB for all CKD patients regardless of race and with an ACR
>30 mg/g to improve kidney outcomes.
47 Reductions in proteinuria and a decreased
rate of decline in eGFR have been observed with ACEIs and ARB in patients with
46 As a result of these and other studies, ACEIs or ARB
should be considered for all patients with diabetes and AER >30 mg/24 hour, even if
1,47 ACEI and ARBs have similar efficacy in BP reduction when
dosed accordingly. Combination therapy is associated with an increased risk of
dialysis and doubling of SCr and should be avoided.
Additionally, spironolactone in combination with an ACEI or ARB lowers
albuminuria independent of BP control in patients with type 2 diabetes.
the risk of hyperkalemia increases significantly limiting the benefit of this therapy.
Aliskiren, an oral direct renin inhibitor, has demonstrated a reduction in albuminuria
when added to losartan. However, additional studies have resulted in early
termination because of increased risk of adverse events and lack of demonstrable
57 The role of aliskiren is uncertain and benefits do not appear to compare
with ACEI and ARBs. The primary goal in G.B. is to delay development of ESRD
and to reduce the risk of cardiovascular complications and death. Treatment with an
ACEI (e.g., ramipril) should be initiated, because she has substantial albuminuria
(700 mg/day) and an elevated BP. An ARB (e.g., losartan) is a reasonable alternative
to an ACEI in patients with ACEI–induced cough or other adverse effects that do not
cross-react with an ARB. The initial product selected is generally based on tolerance
to therapy and cost. A goal BP for G.B., given the fact that she has diabetes and
kidney disease, is a BP less than 130/80 mm Hg,
1 140/90 mg may be reasonable goal
46 Because the beneficial effects of ACEI therapy occur over the course of
months to years, G.B. must be monitored on a long-term basis for changes in kidney
function and albuminuria and for side effects of therapy, such as hyperkalemia. A
moderate increase in SCr is acceptable with initiation of therapy with ACEIs or
ARBs. Contraindications for the use of ACEIs and ARBs include bilateral kidney
artery stenosis and pregnancy. The risk of hyperkalemia must also be weighed against
the potential beneficial effects of these agents.
Some evidence suggests that a nondihydropyridine calcium-channel blocker (e.g.,
diltiazem, verapamil) may be beneficial alone or in combination with an ACEI.
Diuretics may be considered for patients with diabetic nephropathy and edema,
depending on their degree of kidney function. For patients with kidney disease as
extensive as that observed in G.B. (eGFR <30 mL/minute/1.73 m2
are generally preferred because, unlike thiazide diuretics, they may retain their effect
at this reduced eGFR level (see Chapter 27, Fluid and Electrolyte Disorders, and
Chapter 9, Essential Hypertension). Other antihypertensive agents may be considered
based on response to initial therapy and changes in kidney function. Currently,
clinical studies are examining the use of an aldosterone blocker (spironolactone) and
a selective aldosterone blocker (eplerenone) for use in patients with diabetic
nephropathy and overt proteinuria on maximal doses of both an ACEI and an ARB.
The antiproteinuric effect of these agents has been confirmed by several studies, but
the potential increased risk for hyperkalemia when adding these agents to patients
already taking an ACEI and ARB warrants further evaluation of their use. The effect
on slowing progression of kidney disease has not been evaluated with these agents.
Additionally, G.B. should be counseled regarding an exercise program compatible
with her cardiovascular health and tolerance.
High protein consumption accelerates the progression of diabetic nephropathy,
presumably because of increased glomerular hyperfiltration and intraglomerular
pressure. In patients with overt albuminuria, some evidence indicates that the rate of
decline in eGFR, as well as urinary albumin excretion, can be blunted by restricting
protein intake to 0.8 g/kg/day and maintaining an isocaloric diet.
indicates, however, a beneficial role of dietary protein restriction in diabetic patients
with microalbuminuria. Nonetheless, given the potential benefits to delay progression
of kidney disease, G.B. should be advised to maintain an isocaloric diet with a
protein intake of 0.8 g/kg/day (approximately 10% of daily calories).
typical Western diet is high in protein, some patients may have difficulty complying
with such a low-protein diet because of its perceived unpalatability. Intervention by
a dietitian is recommended to design a feasible dietary regimen limited in protein, yet
consistent with nutritional requirements in a diabetic patient.
FLUID AND ELECTROLYTE COMPLICATIONS
CASE 28-1, QUESTION 5: Assess G.B.’s sodium and water balance. What interventions may be used to
As illustrated in G.B., patients in the latter stages of CKD commonly retain sodium
and water. This is supported by G.B.’s elevated BP, 2+ pedal edema, and mild
pulmonary congestion. Sodium and water retention also lead to weight gain. Early in
the course of CKD, glomerular and tubular adaptive processes develop as an
increase in the fractional excretion of sodium (FENa
patients to maintain relatively normal sodium and water homeostasis. As G.B.’s
normal serum sodium concentration indicates, this value is of little use in establishing
the diagnosis of total body sodium and fluid excess because retention of sodium and
water usually occurs in an isotonic fashion, leaving the serum sodium concentration
relatively normal. Eventually, patients with advanced kidney dysfunction exhibit
signs of sodium and fluid retention because sodium balance is maintained at the
expense of increased extracellular volume, which results in hypertension. Expansion
of blood volume, if not controlled, can cause peripheral edema, heart failure, and
pulmonary edema. Thus, management of sodium and water retention is essential. To
achieve control, most patients with advanced kidney disease are placed on sodium
restriction (2 g/day) and fluid restriction (approximately 1–2 L/day). These
restrictions will depend on the current dietary intake, extent of volume overload, and
urine output, and should be altered according to the special needs of the patient.
Because some patients with advanced kidney disease produce normal amounts of
urine, whereas others may produce less (or no urine for HD patients), fluid
restrictions must be based on urine output. Diuretic therapy, usually with loop
diuretics (e.g., furosemide, bumetanide, torsemide), is often required. Combination
therapy with two different types of diuretics (i.e., loop and thiazide) may be
successful in patients resistant to a single agent; however, limitations in efficacy of
diuretics exist under certain conditions (e.g., a reduced eGFR and hypoalbuminemia),
and these situations must be considered when designing a diuretic regimen. Thiazide
diuretics as single agents are generally not effective when the eGFR is less than 30
, as in G.B. The possible exception is use of the thiazide-like
diuretic, metolazone, which may retain its effect at reduced eGFRs.
failure progresses, manifestations of excess fluid accumulation (i.e., edema,
uncontrollable hypertension) develop that are resistant to more conventional
interventions and dialysis will be required to control volume status.
CASE 28-1, QUESTION 6: G.B. has a serum potassium concentration of 5.3 mEq/L. Describe the
mechanisms by which potassium imbalance occurs in patients such as G.B. who have progressive CKD.
Hyperkalemia can result from a combination of factors, including diminished
kidney potassium excretion, redistribution of potassium into the extracellular fluid
owing to metabolic acidosis, and excessive potassium intake. In G.B., all these
mechanisms are likely to be contributing to hyperkalemia.
Potassium normally is filtered at the glomerulus and undergoes nearly complete
reabsorption throughout the kidney tubule. Distal tubular secretion is the primary
mechanism by which potassium is excreted in the urine. A variety of factors affect
this distal secretion of potassium, including aldosterone, sodium load presented to
the distal reabsorptive site, hydrogen ion secretion, the amount of nonresorbable
anions, urinary flow rate, diuretics, mineralocorticoids, and potassium intake.
Serum potassium concentrations are relatively well maintained within normal limits
in patients with CKD. At eGFR greater than 10 mL/minute/1.73 m2
rare without an endogenous or exogenous load of potassium. This balance is
maintained despite a decreasing nephron population and an overall drop in eGFR
because the remaining nephrons undergo adaptive changes to enhance the distal
tubular secretion of potassium per nephron (i.e., increased fractional excretion of
87 GI excretion of potassium is also important because increased GI
excretion and fecal losses may account for up to 35% of the daily potassium loss in
patients with severe kidney disease. G.B.’s eGFR of 21 mL/minute/1.73 m2
the threshold value for adequate potassium homeostasis. G.B. should be carefully
observed for manifestations of hyperkalemia as her kidney disease progresses.
Additional factors that alter potassium homeostasis include metabolic or
respiratory acidosis. Acidemia can cause a redistribution of intracellular potassium
to the extracellular fluid. G.B. has metabolic acidosis as indicated by serum
bicarbonate of 18 mEq/L. This condition may account for her mildly elevated
potassium concentration. Correction of metabolic acidosis could lower her
potassium concentration. For each 0.1-unit change in blood pH, an inverse
approximately 0.6-mEq/L change in the serum potassium concentration occurs (see
Chapter 26, Acid–Base Disorders).
G.B. is not taking any drugs that could contribute to hyperkalemia, although the
influence of ACEIs and ARB must be considered because they are now advocated for
G.B. to delay progression of kidney disease. Potassium-sparing diuretics triamterene
and amiloride should be avoided and spironolactone used with caution in patients
with severe CKD because they decrease tubular secretion of potassium.
CASE 28-1, QUESTION 7: Is treatment of G.B.’s potassium indicated? How should severe hyperkalemia be
Treatment of hyperkalemia depends on the serum concentration of potassium as
well as the presence or absence of symptoms and electrocardiographic (ECG)
changes. Manifestations of hyperkalemia include weakness, confusion, and muscular
or respiratory paralysis. These symptoms may be absent, especially if hyperkalemia
develops rapidly. Early ECG changes include peaked T waves, followed by
decreased R-wave amplitude, widened QRS complex, and a prolonged P-R interval.
These changes may progress to complete heart block with absent P waves and,
finally, a sine wave. Ventricular arrhythmias or cardiac arrest may ensue if no effort
to lower serum potassium is initiated. However, with a potassium level less than 6
mEq/L, G.B. is unlikely to be experiencing ECG changes.
G.B. has a mild elevation in potassium to 5.3 mEq/L; therefore, no specific
treatment is required. Generally, treatment is unnecessary if the potassium
concentration is less than 6.5 mEq/L and there are no ECG changes. Although this
serum potassium concentration does not require immediate intervention, close
monitoring for hyperkalemia and its manifestations is necessary. This would be
particularly important after starting ACEI therapy, which can contribute to
development of hyperkalemia by decreasing aldosterone production. If potassium
concentrations rise above 6.5 mEq/L, and especially if they are accompanied by
neuromuscular symptoms or changes in the ECG, treatment should be instituted.
Goals of therapy include prevention of adverse events related to excessive
potassium and reduction of serum potassium
concentrations to a relatively normal range. Chronic management involves
prevention of hyperkalemia by limiting potassium intake and avoiding the use of
agents that could elevate potassium levels. This requires regular monitoring of
potassium concentrations. Acute management involves reversal of cardiac effects
with calcium administration and reduction of serum potassium. The latter can be
achieved by shifting potassium intracellularly with administration of glucose and
insulin, β-adrenergic agonists, or alkali therapy (if metabolic acidosis is a
contributing factor) and by removing potassium using exchange resins or dialysis (see
Chapter 27, Fluid and Electrolyte Disorders).
CASE 28-1, QUESTION 8: Assess G.B.’s acid–base status. How should her acid–base disorder be
G.B.’s low blood CO2 content and high chloride concentration are consistent with
metabolic acidosis. Normal buffering of hydrogen ions by the bicarbonate–carbonic
acid system as well as other extracellular and intracellular buffers, including
proteins, phosphates, and hemoglobin, is essential for maintaining normal acid–base
balance (i.e., normal pH). Normal metabolism of ingested food produces
approximately 1 mEq/kg of metabolic acid daily, which must be excreted by the
kidneys (primarily as ammonium ion) to maintain acid–base balance. The kidney is
responsible for reabsorption of bicarbonate and excretion of hydrogen ions through
buffering by ammonia (produced by the kidney) and filtered phosphates. Reduced
bicarbonate reabsorption and impaired production of ammonia by the kidneys are the
major factors responsible for development of metabolic acidosis in advanced kidney
disease. As nephron function declines, production of ammonia is increased to
compensate for a decrease in secretion of hydrogen ions; however, once the maximal
capacity for ammonia production is reached, acidosis develops. Mild
hyperchloremia is generally observed in the earlier stages. As kidney disease
progresses, metabolic acidosis with an elevated anion gap is observed owing to
accumulation of organic acids (see Chapter 26, Acid–Base Disorders). Bone
carbonate stores serve as a source of alkali, but with time cannot compensate for
changes in acid–base balance. Metabolic acidosis can contribute to bone disease by
promoting bone resorption, and it may also influence nutritional status by decreasing
albumin synthesis and promoting a negative nitrogen balance.
Comments
Post a Comment
اكتب تعليق حول الموضوع