Give your kidneys a break: lose some weight

Abstract

The level of proteinuria is one of the most determinant risk factors for the progression of proteinuric renal diseases. Several studies have shown that weight loss, either induced by low calorie diets, physical exercise, or bariatric surgery is accompanied by an important antiproteinuric effect.

Reduction in proteinuria is already observed after a few weeks from the onset of weight loss and it is evident even in patients with modest weight losses. The magnitude of body weight loss and proteinuria decrease show a significant correlation.

Reduction in proteinuria by weight loss has been described in obesity-induced glomerulopathy, obese diabetic patients and overweight or obese patients with different types of chronic proteinuric nephropathies.

Attenuation of the obesity-induced glomerular hyperfiltration, decrease in the activity of renin-angiotensin-aldosterone system and modifications in the serum concentrations of adipocyte-derived cytokine are likely to be involved in the anti-proteinuric effect of weight loss, together with a better control of blood pressure, and improvement of serum lipid profile and insulin sensitivity.

Corticosteroid dosage

There is no standard dosing protocol, but patients with impaired renal function due to biopsy-proven renal sarcoidosis should receive prednisone 0.5 to 1 mg/kg/day, depending on the severity of the disease, in a single dose every morning.

The optimal dosing and duration of maintenance therapy are unknown. Based on studies to date, the initial dosing should be maintained for 4 weeks, after which it can be tapered by 5 mg each week down to a maintenance dosage of 5 to 10 mg/day.4

Patients with a poor response after 4 weeks tend to have a worse renal outcome and are more susceptible to relapse.15 Fortunately, relapse often responds to increased corticosteroid doses.11,15 In the case of relapse, the dose should be increased to the lowest effective dose and continued for 4 weeks, then tapered more gradually.

A total of 24 months of treatment seems necessary to be effective and to prevent relapse.15 Some authors have proposed a lifelong maintenance dose for patients with frequent relapses, and some propose it for all patients.4

DIAGNOSIS OF RENAL SARCOIDOSIS

2. What is the likelihood of finding clinically apparent renal involvement in a patient with sarcoidosis?

  • Greater than 70%
  • Greater than 50%
  • Up to 50%
  • Less than 10%

The prevalence of renal involvement in sarcoidosis is hard to determine due to differences in study design and patient populations included in the available reports, and because renal involvement may be silent for many years.

Recent studies have reported impaired renal function in 0.7% to 9.7% of cases: eg, a case-control study of 736 patients reported clinically apparent renal involvement in 0.7% of patients,5 and in a series of 818 patients, the incidence was 1%.

The prevalence of renal involvement may also be underestimated because it can be asymp­tomatic, and the number of granulomas may be so few that they are absent in a small biopsy specimen. A higher prevalence of renal involvement in sarcoidosis is reported from autopsy studies, although many cases remained clinically silent.

3. What is the most common presentation in isolated renal sarcoidosis?

  • Sterile pyuria
  • Elevated urine eosinophils
  • Renal insufficiency
  • Painless hematuria

Renal manifestations of sarcoidosis include hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and impaired renal function.14 Renal involvement can occur during the course of existing sarcoidosis, at the time of first presentation, or even as the sole presentation of the disease.

Two main pathways for nephron insult that have been validated are granulomatous infiltration of the renal interstitium and disordered calcium homeostasis.11,17 Though extremely rare, various types of glomerular disease, renal tubular defects, and renal vascular involvement such as renal artery granulomatous angiitis have been documented.18

5. How is renal sarcoidosis diagnosed?

  • By exclusion
  • Complete urine analysis and renal function assessment
  • Renal biopsy
  • Computed tomography
  • Renal ultrasonography

The diagnosis of renal sarcoidosis is one of exclusion. Sarcoidosis must be considered in the differential diagnosis of renal failure of unknown origin, especially if disordered calcium homeostasis is also present.

In cases of sarcoidosis with granulomatous interstitial nephritis with isolated renal failure as a presenting feature, other causes of granulomatous interstitial nephritis must be ruled out. A number of drug reactions are associated with interstitial nephritis, most commonly with antibiotics, NSAIDs, and diuretics.

Other causes of granulomatous interstitial infiltrates include granulomatous infection by mycobacteria, fungi, or Brucella; foreign-body reaction such as cholesterol atheroemboli; heroin; lymphoma;

or autoimmune disease such as tubulointerstitial nephritis with uveitis syndrome, granulomatosis with polyangiitis, or Crohn disease.27,28 The absence of characteristic kidney biopsy findings does not exclude the diagnosis because renal sarcoidosis can be focal and easily missed on biopsy.29

Urinary manifestations of renal sarcoidosis are usually not specific. In renal sarcoidosis with interstitial nephritis with or without granulomas, proteinuria is mild or absent, usually less than 1.0 g/day.

11,15,16 Urine studies may show a “bland” sediment (ie, without red or white blood cells) or may show sterile pyuria or microscopic hematuria. In glomerular disease, more overt proteinuria or the presence of red blood cell casts is more typical.

Hypercalciuria, nephrocalcinosis, and nephrolithiasis are nonspecific abnormalities that may be present in patients with sarcoidosis. In this regard, an elevated urine calcium level may support the diagnosis of renal sarcoidosis.

Computed tomography and renal ultrasonography may aid in diagnosis by detecting nephrocalcinosis or nephrolithiasis.

The serum ACE level is elevated in 55% to 60% of patients with sarcoidosis, but it may also be elevated in other granulomatous diseases or in chronic kidney disease from various causes.5 Therefore, considering its nonspecificity, the serum ACE level has a limited role in the diagnosis of sarcoidosis.

6. Which is a first-line therapy for renal sarcoidosis?

  • Corticosteroids
  • Azathioprine
  • Mycophenolate mofetil
  • Infliximab
  • Adalimumab

Treatment of impaired calcium homeostasis in sarcoidosis includes hydration; reducing intake of calcium, vitamin D, and oxalate; and limiting sun exposure.11,31 For more significant hypercalcemia (eg, serum calcium levels {amp}gt;

11 mg/dL) or nephrolithiasis, corticosteroid therapy is the first choice and should be implemented at the first sign of renal involvement. Corticosteroids inhibit the activity of 1-alpha-hydroxylase in macrophages, thereby reducing the production of 1,25-dihydroxyvitamin D.

Chloroquine and hydroxychloroquine have been mentioned in the literature as alternatives to corticosteroids.32 But the effect of these agents is less predictable and is slower than treatment with corticosteroids.

Corticosteroids are the mainstay of treatment for renal sarcoidosis, including granulomatous interstitial nephritis and interstitial nephritis without granulomas. Most patients experience significant improvement in renal function.

How often do I need to have a test for albuminuria (proteinuria)?

It is a test that looks for the presence of albumin in your urine.  Albumin is a type of protein that is normally found in the blood.  Your body needs protein.  It is an important nutrient that helps build muscle, repair tissue, and fight infection.  But protein should be in your blood, not your urine.

One of the main jobs of your kidneys is to filter your blood. When your kidneys are healthy, they keep important things your body needs inside your blood, like protein. They also remove things your body doesn’t need, like waste products and extra water.

If your kidneys are damaged, protein can “leak” out of the kidneys into your urine.  Having protein in your urine is called “albuminuria” or “proteinuria.” 

It may be an early sign of kidney disease, but your doctor will check you again to make sure albuminuria is not caused by something else, like not drinking enough water. If your doctor suspects that you have kidney disease, the urine test for albumin will be repeated.

You will also be given a simple blood test to estimateGFR.  GFR stands for glomerular filtration rate.  Your GFR number tells you how well your kidneys are working.

You may also be given:

  • Imaging tests.  (An ultrasound or CT scan).  This produces a picture of your kidneys and urinary tract.  It can show whether your kidneys have kidney stones or other problems.

  • A kidney biopsy.  This can help find out what caused your kidney disease and how much damage to the kidneys has happened.

People who are at increased risk for kidney disease should have this test as part of routine checkups by a healthcare provider.  Those at increased risk include:

  • People with diabetes

  • People with high blood pressure

  • People with a family history of kidney failure

  • People who are 65 years or older

  • Certain ethnic groups including African Americans, Hispanics, Asians, American Indians

If kidney disease is confirmed, your healthcare provider will create a treatment plan for you.  You may also be asked to see a special kidney doctor called a nephrologist.  Your treatment may include:

  • Medications

  • Changes in your diet

  • Lifestyle changes such as losing extra weight, exercising, and stopping smoking.

Most people with kidney disease do not have symptoms unless the disease is very advanced.  However, you may feel:

  • Swelling

  • Shortness of breath

  • Needing to urinate more often

  • Hiccups

  • Fatigue (feeling tired)

  • Trouble sleeping

  • Nausea and vomiting

  • Dry, itchy skin.

For more information:

  • Speak to your healthcare provider

  • Call the National Kidney Foundation’s toll-free number 1-800-622-9010.

NEW YORK (Reuters Health) — Shedding some excess weight through diet, exercise or surgery may help obese adults with kidney disease ward off further decline in kidney function, research hints.

The kidneys filter waste products from the blood and excrete them in the urine. When damaged, their ability to perform these vital functions is reduced.

More than a third of US adults are either overweight or obese, putting them at increased risk for kidney trouble, not to mention heart trouble and diabetes. Weight loss has been shown to improve control of diabetes, lower blood pressure and cholesterol levels, and reduce the effects of heart disease.

To see if losing weight might also help protect the kidneys, Dr. Sankar Navaneethan, from Ohio’s Cleveland Clinic, and colleagues pooled data from 13 studies that examined the impact on kidney function of weight loss achieved through diet, exercise, or surgery. They report their findings in an upcoming issue of the Clinical Journal of the American Society Nephrology.

The researchers found that, in obese adults with kidney disease, losing weight through diet and exercise reduced one hallmark of kidney damage — namely, excess excretion of protein in the urine — what doctors call “proteinuria.”

Diet- and exercise-induced weight loss may also prevent additional decline in kidney function in obese adults with kidney disease, the researchers found.

Weight loss achieved through surgery, on the other hand, seems to help normalize the rate at which the kidneys filter waste products in obese adults with abnormally high filtration rates — a well-known risk factor for the development of kidney disease.

Currently more than 20 million Americans have chronic kidney disease and it’s estimated that by 2015 there will be more than 700,000 people with the most advanced form of kidney disease known as end-stage renal disease or ESRD.

“The health care costs that are associated with this increase are staggering,” Navaneethan and colleagues note.

In obese adults, weight loss may offer real benefits in terms of the kidneys, in addition to the heart-related benefits of shedding excess pounds, they conclude.

SOURCE: Clinical Journal of the American Society Nephrology, 2009.

GRANULOMATOUS INTERSTITIAL NEPHRITIS

1. Based on the information above, what is the most likely cause of this patient’s kidney disease?

  • Medication
  • Granulomatosis with polyangiitis
  • Sarcoidosis
  • Infection

Granulomatous interstitial nephritis is a histologic diagnosis that is present in up to 1% of renal biopsies. It has been associated with medications, infections, sarcoidosis, crystal deposits, paraproteinemia, and granulomatosis with polyangiitis and also is seen in an idiopathic form.

Medicines implicated include anticonvulsants, antibiotics, NSAIDs, allopurinol, and diuretics.

Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases of renal transplant.1 Granulomas are usually not found on kidney biopsy in granulomatosis with polyangiitis, and that diagnosis is usually made by the presence of antiproteinase 3 antibodies.2

Sarcoidosis is the most likely diagnosis in this patient after excluding implicated medications, infection, and vasculitis and confirming the presence of granulomatous interstitial nephritis on renal biopsy.

HISTOLOGIC FEATURES

4. What is the characteristic histologic feature of renal sarcoidosis?

  • Membranous glomerulonephritis
  • Mesangioproliferative glomerulonephritis
  • Minimal change disease
  • Granulomatous interstitial nephritis
  • Immunoglobulin (Ig) A nephropathy

Granulomatous interstitial nephritis is the most typical histologic feature of renal sarcoidosis.4,20–22 However, interstitial nephritis without granulomas is found in up to one-third of patients with sarcoid interstitial nephritis.15,23

Patients with sarcoid granulomatous interstitial nephritis usually present with elevated serum creatinine with or without mild proteinuria ({amp}lt; 1 g/24 hours).1,15,16 Advanced renal failure (stage 4 or 5 chronic kidney disease) is relatively common at the time of presentation.

1,15,16 In the 2 largest case series of renal sarcoidosis to date, the mean presenting serum creatinine levels were 3.0 and 4.8 mg/dL.11,15 The most common clinical syndrome associated with sarcoidosis and granulomatous interstitial nephritis is chronic kidney disease with a decline in renal function, which if untreated can occur over weeks to months.

Even though glomerular involvement in sarcoidosis is rare, different kinds of glomerulonephritis have been reported, including membranous glomerulonephritis, mesangio­proliferative glomerulonephritis, IgA nephropathy, minimal change disease, focal segmental sclerosis, and crescentic glomerulonephritis.25

SARCOIDOSIS: A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem inflammatory disease of unknown cause, characterized by noncaseating epithelioid granulomas. It can involve any organ but most commonly the thoracic and peripheral lymph nodes.3,4 Involvement of the eyes and skin is also relatively common.

Extrapulmonary involvement occurs in more than 30% of cases of sarcoidosis, almost always with concomitant thoracic involvement.5,6 Isolated extrathoracic sarcoidosis is unusual, found in only 2% of patients in a sarcoidosis case-control study.5

Current theory suggests that sarcoidosis develops from a cell-mediated immune response triggered by one or more unidentified antigens in people with a genetic predisposition.7

Sarcoidosis affects men and women of all ages, most often adults ages 20 to 40; but more recently, it has increased in US adults over age 55.8 The condition is more prevalent in Northern Europe and Japan, and in blacks in the United States.7

How is a urine test done?

A simple urine test can be done in your doctor’s office.  You will be asked to pee into a clean cup called a “specimen cup.”  Only a small amount of your urine is needed (about two tablespoons) to do the test.

Hypercalcemia in sarcoidosis

Sarcoidosis is known to cause hypercalcemia by increasing calcium absorption secondary to 1,25-dihydroxyvitamin D production from granulomas. Our patient’s case is unusual, as renal failure was the sole extrapulmonary manifestation of sarcoidosis without hypercalcemia.

In sarcoidosis, extrarenal production of 1-alpha-hydroxylase by activated macrophages inappropriately increases levels of 1,25-dihydroxyvitamin D (calcitriol). Subsequently, serum calcium levels are increased.

Unlike its renal equivalent, granulomatous 1-alpha-hydroxylase evades the normal negative feedback of hypercalcemia, so that increased calcitriol levels are sustained, leading to hypercalcemia, often accompanied by hypercalciuria.19

Disruption of calcium homeostasis affects renal function through several mechanisms. Hypercalcemia promotes vasoconstriction of the afferent arteriole, leading to a reduction in the GFR. Intracellular calcium overload can contribute to acute tubular necrosis and intratubular precipitation of calcium, leading to tubular obstruction.

Hypercalciuria predisposes to nephrolithiasis and obstructive uropathy. Chronic hypercalcemia and hypercalciuria, if untreated, cause progressive interstitial inflammation and deposition of calcium in the kidney parenchyma and tubules, resulting in nephrocalcinosis. In some cases, nephrocalcinosis leads to chronic kidney injury and renal dysfunction.

KEY POINTS

  • Sarcoidosis is a multisystem granulomatous disease that most commonly involves the lungs, skin, and reticuloendothelial system.
  • Renal involvement in sarcoidosis is likely underestimated due to its often clinically silent nature and the possibility of missing typical granulomatous lesions in a small or less-than-optimal biopsy sample.
  • Manifestations of renal sarcoidosis include disrupted calcium homeostasis, nephrocalcinosis, nephrolithiasis, and renal failure.
  • Because the clinical and histopathologic manifestations of renal sarcoidosis are nonspecific, the diagnosis is one of exclusion. In patients with renal failure or with hypercalcemia or hypercalciuria of unknown cause, renal sarcoidosis should be included in the differential diagnosis. Patients with chronic sarcoidosis should also be screened for renal impairment.
  • Granulomatous interstitial nephritis is the classic histologic finding of renal sarcoidosis. Nonetheless, up to one-third of patients have interstitial nephritis without granulomas.
  • Corticosteroids are the mainstay of treatment for renal sarcoidosis. An initial dose of oral prednisone 0.5 to 1 mg/kg/day should be maintained for 4 weeks and then gradually tapered to 5 to 10 mg/day for a total of 24 months. Some patients require lifelong therapy.
  • Several immunosuppressive and cytotoxic agents may be used in cases of corticosteroid intolerance or to aid in effective taper of corticosteroids.
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