Hospital Medicine

Diabetic nephropathy

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Diabetic nephropathy

I. What every physician needs to know.

Due to increase in type 2 diabetes, the prevalence and incidence of diabetes has grown. This increase has affected the development of diabetic kidney disease. Patients with diabetes are at risk for diabetic kidney disease but may also develop non-diabetic kidney disease. Correctly diagnosing the form of chronic kidney disease a diabetic patient has will aid in guiding the management for these patients.

Diabetic nephropathy is a form of chronic kidney disease that occurs after the kidney is exposed to persistent hyperglycemia. It affects 20-40% of patients with diabetes mellitus. Patients are now diagnosed with diabetic nephropathy when they have evidence of proteinuria and reduced glomerular filtration rate.

II. Diagnostic Confirmation: Are you sure your patient has diabetic nephropathy?

The gold standard for diagnosis is a kidney biopsy. However, the diagnosis can be made in most cases without a kidney biopsy.

Albuminuria is often the first clinical indicator of the presence of diabetic kidney disease and is a marker for glomerular disease Albuminuria should be measured more than once as increases can be seen with hyperglycemia, elevated blood pressures, increases in dietary protein, and fever, for example. Albuminuria may be measured through a spot albumin-to-creatinine ratio or by 24-hour urine collection. More than one sample should be obtained three-six months apart for confirmation of increased albuminuria. The presence of albuminuria of >300 mg/g creatinine and the presence of retinopathy is strongly suggestive of DKD.

Other findings that can help in the diagnosis are elevated hemoglobin A1c (HbA1c) usually greater than 8, hypertension that is elevated out of proportion to the kidney disease, and lack of hematuria. A urinalysis would demonstrate proteinuria with no other urine sediment.

The following suggests non-diabetic kidney disease: absence of diabetic retinopathy, low or rapidly decreasing GFR, rapidly increasing proteinuria, refractory hypertension, presence of active urinary sediment (i.e. hematuria), signs or symptoms of other systemic disease, or >30% reduction in GFR within 2-3 months after starting an ACE inhibitor or ARB.

A. History Part I: Pattern Recognition:

The stage of kidney disease will directly correlate with a patient's symptoms. Initially patients may notice they are urinating more frequently, especially at night, despite having well-controlled blood glucose levels. They may notice frothy urine. As the kidney disease progresses, they may develop nausea, vomiting and anorexia due to uremia, notice leg cramps, or feel weak. In the later stages of disease, patients may notice leg swelling or periorbital swelling.

B. History Part 2: Prevalence:

Diabetes is the leading cause of end-stage renal disease (ESRD) and accounts for nearly 50% of cases in the developed world. Patients that are most at risk of developing diabetic nephropathy and ESRD include African Americans, Hispanic or Native Americans. Additional risk factors for developing diabetic kidney disease include the following:

  • age

  • family history of kidney disease or high blood pressure

  • poorly controlled blood sugars

  • poorly controlled blood pressure

  • duration of diabetes

  • history of smoking

  • high normal urine albumin.

C. History Part 3: Competing diagnoses that can mimic diabetic nephropathy

Diabetic patients can present with both diabetic and non-diabetic kidney disease. Competing diagnoses with diabetic nephropathy are immunoglobulin A (IgA) nephropathy, membranous nephropathy, mesangial proliferative glomerulonephritis (GN), and minimal change disease. Kidney biopsy is the gold standard for differentiating between these diseases. However, the rate of progression of the kidney disease and the length of time a patient has had diabetes are helpful in differentiating the diagnoses.

Urinalysis is also helpful in making the diagnosis. The urinalysis in diabetic nephropathy contains urinary albumin and/or protein. Urinary RBC and RBC casts have been reported in up to 30% of cases, but it is not typical of the disease and other diagnoses should be ruled out.

These diseases have hematuria: IgA nephropathy and mesangial proliferative glomerulonephritis. In minimal change disease, oval fat bodies appear as Maltese crosses on examination of the urine under a polarized lens.

D. Physical Examination Findings.

Diabetic kidney disease is asymptomatic in the early stages. Later in the disease, a patient may develop signs of chronic kidney disease and can include pale conjunctiva and peripheral edema, particularly periorbital edema. The majority of patients with diabetic nephropathy have diabetic retinopathy.

Patients can also be assessed for peripheral neuropathy through vibratory sensory loss in ankles and great toe as well as sensory loss through fine pinprick. Patients should have their feet assessed for lesions that may have occurred due to their sensory loss.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

These tests should be ordered to establish the diagnosis:

  • Hemoglobin A1C test

  • Basic metabolic panel (BMP) with calculation of GFR. The GFR is often elevated in the early years of the disease (greater than 90ml/min). After the first few years, the GFR slowly declines

  • Urinalysis with microscopy. This will show proteinuria with no RBC and no granular casts.

  • Each diabetic should be tested for albuminuria. Patients with type 2 diabetes should be screened yearly from the time of diagnosis, and those with type 1 diabetes should be screened 5 years after the time they are diagnosed.

  • If albuminuria of >30 mg/g creatinine is present, this test should be repeated in 3-6 months to confirm diagnosis of increased albuminuria.

Additional laboratory values should be obtained if chronic kidney disease is present.

  • A complete blood count (CBC) should be ordered to assess for anemia of chronic kidney disease. Erythropoeitin excretion is usually affected by the time patient reaches stage 2 kidney disease (when the GFR is less than 45).

  • Parathyroid hormone (PTH) test should be ordered. Ordering this test will give the information necessary to determine if the patient has the appropriate calcium balance. The kidneys play a major role in the body's calcium hemostatsis by converting 25 dihydroxyvitamin D from the diet to 1,25 dihydroxyvitamin D when the kidneys begin to fail and the calcium level in the blood decreases because the kidneys are no longer able to complete the conversion. PTH is the hormone that permits reabsorption of calcium from our bone and therefore keeps calcium at the appropriate level. If PTH level is elevated, supplementation with vitamin D may be indicated.

The following tests should be ordered to rule out other possibilities.

  • Hepatitis serology panel testing should include hepatitis A, B and C.

    • Fulminate Hepatitis A can cause acute renal failure in rare cases.

    • Hepatitis B is associated with membranous glomeronephritis, membranoproliferative nephritis. However, kidney disease from hepatitis B is rarely seen in the United States because renal involvement is typically seen in patients who acquired Hepatitis B as children. The vast majority of patients who acquire Hepatitis B in the United States are adults.

    • Hepatitis C is associated with mixed cryoglobulinemia, membranoproliferative glomerulonephritis, membranous nephropathy and polyarteritis nodosa.

  • Cryoglobulins, particularly C3 and C4 should also be ordered.

  • Human immunodeficiency virus (HIV) testing, If the antibody testing is positive then a HIV polymerase chain reaction (PCR) should be ordered.

  • Anti-nuclear antibody (ANA) testing should be ordered if the diagnosis of cause for the renal dysfunction has not been determined. If the ANA titer is greater than 1:80 then vasculitis is a possibility and further testing is necessary to rule out systemic lupus erythematosus (SLE) etc.

  • Liver function tests, platelet count and international normalized ratio (INR) should be assessed to ensure that the liver function is intact. If not, then hepatorenal syndrome is a possibility.

  • If one is trying to differentiate diabetic nephropathy from intravascular depletion calculating a fractional excretion of sodium should be helpful.

  • Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) should be ordered to rule out secondary amyloid process.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Renal ultrasound should be ordered in patients with suspected obstruction. Autonomic instability can occur after years of diabetes and could lead to urinary retention and hydronephrosis. In early diabetic kidney disease the findings on ultrasound kidneys are often normal or slightly large in size. As the disease progresses, the kidneys become atrophied and smaller in size.

3. When should a renal biopsy be obtained to establish the diagnosis?

Renal biopsy should be considered in diabetic patients with chronic kidney disease (reduced GFR <60 mL/min per 1.73 m2) and the following features:

  • Absence of diabetic retinopathy

  • Short duration of diabetes (<5 years)

  • Absence of typical chronology, e.g. acute onset of proteinuria, rapid decline in renal function

  • Presence of hematuria

  • Presence of other systemic disease

  • Nephrotic syndrome

Findings on biopsy of of diabetic nephropathy or diabetic kidney disease is variable. The reason for variation in kidney changes in unclear. In 2010, a new pathological classification of DKD was proposed for patients with diabetes based on glomerular features:

Class I: Glomerular basement membrane (GBM) thickening, diagnosed by transmission electron microscopy.

Class II: Mesangial expansion – A: mild; B: severe.

Class III: Nodular glomerulosclerosis (Kimmelstiel–Wilson lesion).

Class IV: Advanced diabetic glomerulosclerosis (>50% global glomerulosclerosis).

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A computed tomography (CT) scan of the abdomen is unnecessary and often ordered.

III. Default Management.

The severity of the kidney disease will guide next steps for management. If diabetic nephropathy is diagnosed through screening and in the early stages, medical management may be initiated. If a reduced GFR is seen on lab values, determination of the acuity of renal dysfunction is needed.

If acute renal failure is suspected, the patient may benefit from close monitoring including strict recordings of intake and urine output, daily weights, daily laboratory monitoring and further investigation. Medication adjustments may be needed depending on GFR. Patients should be assessed for volume overload such as peripheral or pulmonary edema. A urinalysis with microscopy should be done to assess for protein, RBC and sediment. Liver function tests (LFTs) should be ordered in order to determine any form of liver disease that could be contributing to the kidney disease. If abnormalities in the LFTs are found it should prompt further testing for liver disease that would help determine the origin of the liver dysfunction as well as any possible alternative cause for the kidney disease. A renal ultrasound should be obtained to determine the size of the kidney. A bladder scan should be obtained. If the patient describes symptoms of urinary retention as diabetics are at risk for autonomic dysfunction. If there is greater than 400cc of urine, a Foley catheter should be placed.

Changes from baseline in a patients BMP or if medications are started that could affect electrolytes then the BMP should be obtained daily. Also, keep in mind that patients with diabetic nephropathy are at risk for developing type 4 (RTA) which could lead to hyperkalemia even with a normal creatinine. Any drug that can worsen renal failure should be stopped. Examples of these drugs include angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs), etc. The amount of insulin given should be reduced in patients whose GFR is decreasing as insulin is renally excreted and has a longer half-life in these patients.

A. Immediate management.

Administer diuretics if the patient is volume overloaded and is having difficulty breathing from pulmonary edema.

If a patient is not in acute renal failure, consider starting an ACEI or ARB if the patient has albuminuria and hypertension (BP>140/90). They should be started with caution in a patient with a reduced GFR. When started, the serum creatinine and potassium levels must be monitored. If the patient is in acute renal failure, then these drugs should be initiated when the creatinine is stable.

B. Physical Examination Tips to Guide Management.

N/A

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

After initiation of new medications, a BMP should be obtained to assess that creatinine, GFR, and potassium remain stable. If an ACEI or ARB has been started, the GFR should not rise more than 20%. If a rise is seen, the ACEI should be discontinued and alternative causes of chronic kidney disease should be explored. Urinary output should remain greater than 400cc per day.

The benefits of serial monitoring of albuminuria remain in question. Continued monitoring of urine albumin excretion may help to assess a response to medications or progression of the disease.

D. Long-term management.

According to the most recent Joint National Committee (JNC8) guidelines, blood pressure should be reduced to below 140/90 mmHg to decrease chronic kidney disease progression. Renin-angiotensin-aldosterone system (RAAS) blockade is the preferred method to reduce chronic kidney disease in patients with albuminuria, hypertension and diabetes. Medications such as ACE inhibitor and angiotensin receptor blockers should be considered. If dual RAAS blockade is used (ACE inhibitory and ARB), close monitoring of potassium and kidney function is recommended.

A cholesterol panel should be obtained. In the general population and in diabetics, LDL is followed as a risk factor for cardiovascular disease. However, in patients with non-dialysis dependent CKD, statins are recommended independent of LDL goals as cardiovascular events and mortality are reduced with these medications. Lipid panels may be monitored to assess adherence to medication regimen but no special goal is recommended.

Measurement of glycemic control over time is recommended to prevent progression of CKD as well. Patients with GFR levels <60 are more susceptible to hypoglycemia. Also, A1C levels can become lower as GFR levels fall due to anemia associated with chronic kidney disease and the initiation of erythrocyte-stimulating agents. Measurement of A1C should still be performed and adjustments in diabetes treatment may be needed. A1C goal should be <8 if GFR is <60. Monitoring with blood glucose checks may be beneficial in chronic kidney disease and ESRD given the limitations of the A1C.

E. Common Pitfalls and Side-Effects of Management

Patients with acute renal failure or rising creatinine develop hypoglycemia frequently. In patients on insulin and/or receiving oral glycemic agents, the half-life of these agents are increased.

In acute renal failure, patients receiving ACEI and ARBs should have these agents stopped. They can be restarted once the creatinine stabilizes.

In the hospital, oral hypoglycemic agents are discouraged. However, when used in diabetic patients with chronic kidney disease, the following precautions should be taken into account.

  • Metformin is contraindicated when the creatinine is greater than 1.5 in men and 1.4 in women

  • Sulfonyureas: glyburide does not need dose adjustment, glyburide should be avoided in CKD

  • TZDs are metabolized by the liver but can lead to fluid retention

  • Alpha-glucosidase inhibitors should be avoided in GFR<30

  • All of the DPP-4 inhibitors can be used in CKD but some may require dose titration

  • SGLT2 inhibitors may need dose adjustment

In patients with stage 3 to stage 5 chronic kidney disease, there is an increased risk of hypoglycemia secondary to decreased insulin clearance into the urine and impaired gluconeogenesis from the kidney. Therefore insulin dose should decrease as the patient's GFR decreases.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Management as described above.

B. Liver Insufficiency.

If liver insufficiency is present and the diagnosis of diabetic nephropathy has not been determined, then the reason for the renal failure needs to be assessed by the serologies listed above. Patients with liver disease, especially cirrhosis, are at higher risk for hypoglycemia.

C. Systolic and Diastolic Heart Failure

Patients with systolic or diastolic heart failure and diabetic nephropathy need tight blood pressure control. All these patients should be on an ACEI or ARB. Thiazolidinedione (TZD) should be avoided in patients with heart failure.

F. Malignancy

Patients with malignancy and chronic renal failure are at increased risk of deep vein thrombosis (DVT) and pulmonary embolism. If any extremity is swollen, it should be scanned for DVT. Patients that develop nephrotic range proteinuria lose antithrombin, protein C, and protein S in their urine and therefore become prothrombotic.

G. Immunosuppression (HIV, chronic steroids, etc.).

Steroids can led to hyperglycemia and therefore increase proteinuria. The patient's GFR can initially increase before become worse. Tight glycemic control alleviates this complication.

H. Primary Lung Disease (COPD, Asthma, ILD)

If patients are smoking, then advise them that given the comorbidity of diabetes they are at increased risk of cardiovascular disease. When these patients are placed on steroids they also often develop hyperglycemia that can lead to an increase in proteinuria and adverse effects on the kidney. Diagnosis of diabetic nephropathy should be confirmed with repeat albuminuria measurements when off steroids and/or acute illness has resolved.

I. Gastrointestinal or Nutrition Issues

Patients with chronic renal failure should be placed on low protein diets (no more than 0.8-1.0gram/kg/day).

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Blood pressure should be controlled to avoid further rises in creatinine and reduction in GFR. Consider GFR when initiating new medications, as renal adjustment may be needed.

B. Anticipated Length of Stay.

The length of stay depends on comorbidities. Patients are rarely hospitalized solely for diabetic nephropathy and diabetic nephropathy is a slowly progressive chronic disease.

C. When is the Patient Ready for Discharge.

Patients are ready for discharge when their creatinine is stable.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Patients should follow up with their primary care physician within 1 week of discharge. If their creatinine clearance is significantly reduced to stage 3 or greater, they should be seen by a nephrologist within 1 week of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Tests to be conducted prior to discharge are:

  • BMP

  • Urinalysis with microscopy

  • Lipid panel

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

BMP to evaluate any changes in potassium, creatinine and GFR especially if an ACEI or ARB was started in the hospital.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counselling.

End stage renal disease (ESRD) is a major cause of death, accounting for 59-66% of deaths in type 1 diabetes. The five year survival rate in the elderly once the patient is placed on dialysis has been reported to be as low as 10% and in the younger type 1 diabetic 40%. Both type 1 and type 2 diabetes lead to ESRD, although the majority of patients on dialysis are type 2. The higher prevalence of type 2 diabetics accounts for their larger number on dialysis. Type 2 diabetes prevalence is 5-10 fold greater than type 1. Some 20-40% of patients with type 1 diabetes advance to ESRD as oppose to 10-20% of patients with type 2 diabetes.

Cardiovascular disease is a major cause of death in patients with diabetic nephropathy, especially in those with type 1 diabetes. Proteinuria is a predictor of mortality. Patients with proteinuria have a 40 fold higher mortality rate over patients who do not have proteinuria. Microalbuminuria independently predicts cardiovascular morbidity. It also is a predictor of all-cause mortality.

Given these details, to decrease morbidity and mortality, all patients should be asked to control their blood sugar, blood pressure and take their ACEI/ARB when appropriate.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

To reduce risk of readmission requires:

  • blood glucose control

  • blood pressure control

  • stable GFR.

VII. What's the evidence?

"American Diabetes Association: Diabetes Care". vol. 34. 2011.

Kromhout, D, Giltay, EJ, Geleijnse, JM. "Alpha Omega Trial Group: n-3 fatty acids and cardiovascular events after myocardial infarction". N Engl J Med. vol. 363. 2010. pp. 21.

Wolf, G, Ritz, E. "Diabetic nephropathy in type 2 diabetes prevention and patient management". J Am Soc Nephrol. vol. 14. 2003. pp. 1396-1405.

Cooper, ME. "Pathogenesis prevention and treatment of diabetic nephropathy". Lancet. vol. 352. 1998. pp. 213-9.

"National Kidney Foundation NKF-KDOQI Guidelines".

Tuttle, K. "Diabetic Kidney Disease: A Report from an ADA Consensus Conference". Diabetes Care. vol. 37. 2014. pp. 2864-2883.

"Executive Summary: Standards of Medical Care in Diabetes – 2014". Diabetes Care. vol. 27. Jan 2014. pp. S5-13.

Maclsaac, R, Ekinci, E, Jerums, G. "Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease". Am J Kidney Dis. vol. 63. 2014. pp. S39-S62.

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