Usmle hot points review

Danil Hammoudi.MD

 

 

1/ Fanconi’s syndrome

 

renal tubular defect, spare the glomeruli but result in a generalized pattern of tubular dysfunction  may lead to the loss of:

·        Phosphate

·        Calcium

·        Glucose

·        Amino acids

Result : OSTEOMALACIA and RICKETS

·        excessive urine production and urination

·        excessive thirst;

·        dehydration;

·        constipation;

·        anorexia nervosa;

·        vomiting;

·        elevated levels of glucose, phosphate, calcium, uric acid, amino acids, and protein (especially beta2-microglobulin and lysozyme) in the urine;

·         elevated levels of chloride

·         decreased levels of phosphate and calcium in the blood;

·         excessively acidic blood.

 

Pathogenesis

• in the Primary form, there appears to be two pathophysiologic mechanisms:
  • 1. defective intracellular production or transfer of energy
  • 2. absence of proximal tubular brush borders (congenital defect in the biochemical synthesis of brush-border constituents)
• both mechanisms result in an impaired reabsorption of amino acids, bicarbonate, glucose, and phosphate
  • loss of HCO3 in the urine leads to a proximal RTA
  • renal K loss is secondary to the flooding of the distal tubule with HCO3 which stimulates sodium reabsorption in exchange for potassium leading to hypokalemia
  • contraction of the extracellular volume stimulates chloride reabsorption resulting in hyperchloremia and secretion of aldosterone leading to further potassium loss
  • phosphaturia -> hypophosphatemia + metabolic acidosis ->
    • rickets +/- osteomalacia
    • osteoporosis +/- pathological fractures
  • Vitamin D resistance may be due to impaired conversion of Vitamin D -> 1,25 (OH)2D3 by abnormal proximal tubular cells in the presence of metabolic acidosis

 

This reabsorption step is defective in Fanconi's syndrome.

As a consequence, substances that are normally reabsorbed, like glucose, amino acids, small proteins, water, calcium, potassium, magnesium, bicarbonate, and phosphate, are lost and the body becomes overly acidic.

The most noticeable indirect consequences of impaired reabsorption are the bone diseases, rickets and osteomalacia

. Rickets affects children and is associated with bone deformities, failure to grow, and difficulty walking.

 If a person acquires Fanconi's syndrome as an adult, the bone disease is termed osteomalacia and is accompanied by severe bone pain and spontaneous fractures.

Unlike rickets due to malnutrition, these diseases cannot be reversed with vitamin D.

Muscle weakness and occasional paralysis are other indirect consequences of the ineffective reabsorption

The genetic diseases known to give rise to Fanconi's syndrome are

·        cystinosis (the most common cause in children),

·        galactosemia,

·        glycogen storage disease,

·         hereditary fructose intolerance,

·         Lowe syndrome,

·        Wilson disease,

·        tyrosinemia,

·         medullary cystic disease,

·         vitamin D dependency,

·        familial idiopathic Fanconi's syndrome

 

Environmental assaults that cause Fanconi's syndrome include :

·        exposure to heavy metals (like cadmium, lead, mercury, platinum, uranium),

·        certain drugs (like outdated tetracycline and gentamicin),

·         other substances (like Lysol, paraquat, toluene, the amino acid lysine taken as a nutritional supplement),

·        kidney transplantation

Fanconi's syndrome is also known as Fanconi syndrome, renal Fanconi syndrome, Fanconi renaltubular syndrome, and Lignac-de Toni-Debre-Fanconi syndrome. Fanconi's anemia is, however, a totally different disease.

CAUSES: multiple myeloma amyloidosis sjogren's syndrome nephrotic syndrome renal transplantation vitamin D deficiency lead mercury cadmium uranium strontium tetracycline maleic acid cystinosis wilson's disease galactosemia hereditary fructose intolerance tyrosinemia lowe's syndrome types of insults: 1. Primary Fanconi Syndrome 1. Sporadic 2. Hereditary autosomal dominant autosomal recessive x-linked recessive 2. Secondary Fanconi Syndrome 1. Inborn Errors of Metabolism Cystinosis Galactosemia I & III Glycogenosis - GSD Ia & XI Hereditary Fructose Intolerance Lowe Syndrome Tyrosinemia I Wilson Disease 2. Acquired Diseases 1. Proteinuric States Multiple Myeloma Nephrotic Syndrome 2. Tubular Toxins heavy metals (cadmium, lead, mercury) drugs (outdated tetracycline, gentamicin, azathioprine) 3. Others Hyperparathyroidism (Primary & Secondary) Interstitial Nephritis Transplanted Kidney Tumors Vitamin D Dependant Rickets

INVESTIGATIONS:

1. Serum

• normal anion gap hyperchloremic metabolic acidosis (with low serum bicarbonate)
• normal or low amino acids
• normal glucose
• hypophosphatemia, hypokalemia, hypouricemia
• elevated alkaline phosphatase

2. Urine

1. Cardinal Features

• generalized (non-specific) hyperaminoaciduria
• glucosuria
• phosphaturia
• pH <5.5

2. Others

• bicarbonaturia, hyperkaliuria, uricosuria, tubular protein-uria, carnitinuria, low urinary ammonia
• hyposthenuria (low specific gravity)

3. Imaging Studies

1. Skeletal X-Rays

• rickets, osteopenia, or osteoporosis

 

Fanconi’s syndrome :aquired

·        An inherited blood disease

·        bone marrow fails to produce all types of blood cells.

·        Lack of white blood cells results in predisposition to infections,

·        while lack of platelets and red blood cells result in bleeding, and fatigue (anemia), respectively.

·        It is also associated with a broad variety of physical anomalies.

·        (Fanconi’s anemia is distinct from Fanconi’s syndrome, a rare kidney disorder in which nutrients are lost through the urine.)

• patients with Fanconi’s anemia remain predisposed to leukemia (develops in 10-15% of patients), myelodysplastic syndrome, liver cancer and other cancers

 

• pregnant.they often require transfusion support throughout pregnancy.
• Fertility is decreased in males, although a small number of Fanconi’s patients have fathered children

 

Fanconi's syndrome; familial

Alternative names:

deToni-Debre-Fanconi syndrome

Fanconi syndrome is an impairment in proximal tubular function of the kidney.

 This impairment causes certain compounds, which should be absorbed back into the bloodstream by the kidneys, to be excreted in the urine instead.

Some compounds that may be lost in the urine include glucose, amino acids, uric acid, and phosphate. Loss of these compounds can cause problems such as

·        growth failure,

·        decreased bone mineralization (rickets),

·        and abnormal bone mineralization (osteomalacia).

·        Type two renal tubular acidosis (RTA) occurs when too much bicarbonate is excreted in the urine, causing excess acid in the blood (acidosis).

·         Another problem that may result is dehydration caused by excess urination.

Causes:

Fanconi syndrome can be genetic or acquired later in life.

  Common causes of Fanconi syndrome in children are genetic defects impairing the body’s ability to break down certain compounds, such as

·        the amino acid cystine (Cystinosis),

·        fructose (fructose intolerance),

·        galactose (galactosemia),

·         glycogen (glycogen storage diseases).

·          Cystinosis is the most common cause of Fanconi syndrome in children.

·          Lowe’s disease (oculocerebrorenal syndrome), a rare genetic disorder of the eyes, brain, and kidneys, can also cause Fanconi syndrome.

·          Another genetic defect that can cause Fanconi syndrome is Wilson’s disease, which causes copper to collect in the kidneys, liver, eyes, and other organs.

·          Similarly, exposure to heavy metals, such as lead poisoning, can cause Fanconi syndrome, even when there is no genetic disease.

 

 

·        In adults, Fanconi syndrome can be caused by various acquired disorders that damage the tubules of the kidneys. 

·        As in children, this damage can be caused by exposure to heavy metals such as lead, mercury, and cadmium.

·        The kidneys can also be damaged by prescribed drugs such as cidofovir (used to treat AIDS-related cytomegalovirus disease),

·        gentamicin, tetracycline used after its expiration date, and azathioprine (used to suppress the immune system after organ transplantation or to treat certain autoimmune disorders).

·        Kidney damage leading to Fanconi syndrome can also be caused by dysproteinemias, diseases in which there are abnormal protein deposits in the kidney. 

·        These include multiple myeloma, light chain deposition disease, and primary amyloidosis.

·        It can also occur as a result of a kidney transplant.  Sometimes, in both children and adults, the cause of Fanconi syndrome is not known. 

Symptoms:

• Excess amounts of the following substances in the urine:  amino acids, glucose, phosphate, magnesium, potassium, bicarbonate and sodium.
• Growth failure
• Rickets in children
• Osteomalacia in adults (abnormal bone mineralization, causing an increased incidence of fractures)
• Dehydration due to excess urination

Treatment:

Many different diseases can cause Fanconi syndrome. 

  The underlying disease should be treated if there is a treatment available.  For example:

• Wilson’s disease is treated with D-penicillamine, which binds excess copper in the blood
• Cystinosis is treated with cysteamine, which removes cystine from the body.

Most disorders causing Fanconi syndrome cannot be treated directly. 

 In these cases, the symptoms of the disease are treated instead.

  Symptomatic therapy includes:

• Alkali therapy, which treats acidosis by increasing the pH of the blood
• Replacement of electrolytes such as potassium, phosphate, calcium and magnesium
• Supplementing the diet with Vitamin D to prevent rickets and osteomalacia

 

1. Primary Fanconi Syndrome

1. Medical

• oral alkalinizing supplements
  • Shohl solution (sodium citrate)
  • sodium bicarbonate tablets in older patients
• oral phosphate supplements
  • Polycitra (potassium citrate)
• vitamin D supplements

2. Prognosis

• may resolve spontaneously over the first decade

2. Secondary Fanconi Syndrome

• treat underlying disorder

 

Prognosis

Fanconi's syndrome can be reversible. Fanconi's syndrome caused by kidney transplantation usually reverses itself within the first year after transplant surgery.

When caused by a toxin in the environment, Fanconi's syndrome generally can be reversed by removing the causative agent from the patient's environment.

 If it is caused by a genetic disease, it can usually be reversed by treating the disease.

However, if Fanconi's syndrome is not treated or if treatment is unsuccessful, the kidneys can fail.

  Key Terms

•  Acidosis

Condition where the body is more acidic than normal; associated with headache, nausea, vomiting, and visual disturbances.

•  Fanconi's anemia

An inherited form of aplastic anemia.

•  Filtrate

The part of filtered material that flows through the filter.

•  Idiopathic

Refers to a disease of unknown cause.

•  Polydipsia

Excessive thirst.

•  Polyuria

Excessive production of urine.

 

TO RESUME

I.            Pathophys                              A.            Deficient Renal Tubular excretion                              B.            Results in:                                                       1.            Aminoaciduria                                                       2.            Glycosuria                                                       3.            Hypophosphatemia Causes Hereditary idiopathic form Acquired form Medications Heavy metals Multiple Myeloma Amyloidosis Renal transplantation Sx Children Polydipsia Malnutrition Increased susceptibility to infection Adults Pain in weight bearing joints Dehydration Signs Growth Retardation Developmental Delay Bony deformities similar to Rickets Waddling gait Pathologic fractures Lab Urine Aminoaciduria Cystinuria Glycosuria Phosphaturia

         I.            GLYCOSURIA

       II.            Hyperglycemia Causes of glucose in urine

                             A.            See Hyperglycemia

3. Renal Causes of glucose in the urine
   1. Signs suggestive of Renal Tubular disease
      1. Serum Glucose <180 mg/dl
      2. Glucose Tolerance Tests are normal
      3. Ketosis absent
   2. Specific Causes
      1. Fanconi's Syndrome
      2. Toxic renal tubular disease
         1. Lead toxicity
         2. Mercury toxicity
         3. Degraded Tetracycline
      3. Inflammatory renal disease
         1. Acute Glomerulonephritis
         2. Nephrosis
      4. Increased GFR without tubular damage
4. False Positive Glucosuria
   1. Ascorbic acid
   2. Nalidixic acid
   3. Cephalosporins
   4. Probenacid

HYPOPHOSPHATEMIA

         I.            Causes

                             A.            Starvation

                             B.            Diabetic Ketoacidosis

                            C.            Total Parenteral Nutrition (TPN)

                            D.            Insulin

                             E.            Nasogastric Suction (NG Suction)

                             F.            Diuretics

                            G.            Vomiting

                             H.            Vitamin D deficiency

                                 I.            Hypoparathyroid

                              J.            Pseudohypoparathyroid

                             K.            Medications

                                                      1.            Corticosteroids

                                                      2.            Aluminum Hydroxide antacids

                              L.            Gram negative sepsis

2. Evaluation
   1. Check Urinary Phosphate excretion (Urine pHosphorus)
   2. Low Urine pHosphorus: under 100 mg/d (FePO4 under 10%)
      1. Internal Redistribution
         1. Glucose administration
         2. Alkalosis
         3. DKA recovery
      2. GI Losses
         1. Malabsorption
         2. Vomiting
         3. Diarrhea
         4. Aluminum or Magnesium antacids
   3. High Urine pHosphorus: over 100mg/d (FePO4 over 20%)
      1. Check for wasting in urine of other electrolytes
         1. Glucose
         2. Amino acid
         3. Uric Acid
         4. Bicarbonate
      2. Electrolyte Wasting present
         1. Fanconi's Syndrome
            1. Idiopathic
            2. Sporadic
            3. Familial
         2. Cystinosis
         3. Amyloidosis
         4. Multiple Myeloma
         5. Wilson's Disease
         6. Nephrotic Syndrome
         7. Cadmium toxicity
         8. Acute lead toxicity
      3. Electrolyte Wasting absent
         1. Increased Serum Calcium
            1. Primary or ectopic Hyperparathyroidism
         2. Normal or Low Serum Calcium
            1. Secondary Hyperparathyroidism
            2. Androgen or Estrogen treatment
            3. Thiazide Diuretics
            4. Vitamin D resistant rickets
            5. Post Acute Tubular Necrosis
            6. Post-transplant
3. Management
   1. SEE Phosphorus Replacement