Renal and Glomerular Disorders

• Renal diseases can be glomerular, tubular, or interstitial.

Introduction

• Urinalysis provides information about renal disease and may shed light on metabolic diseases.
• Urinalysis can detect abnormalities before the appearance of symptoms.
• Urinalysis is a tool for monitoring disease progression and therapy effectiveness.
• Disorders throughout the body can affect renal function and lead to abnormalities in urinalysis.
• The kidneys are consistently exposed to potentially damaging substances.

Glomerular Disorders

• Glomerular disorders originate from renal disease of glomerular origin.
• Most disorders associated with the glomerulus are of immune origin.
• Immune complexes from immunologic reactions deposit throughout the body.
• Increased serum immunoglobulins get deposited on glomerular membranes.
• Immune system mediators such as complement migrate and cause changes in and damage to membranes.
• Non-immunologic causes of glomerular disorders include exposure to chemicals and toxins with nephrotic syndrome being one cause.

Glomerulonephritis (GN)

• Glomerulonephritis (GN) is an inflammatory process affecting the glomerulus.
• Glomerulonephritis has findings of blood, protein, and urinary casts.
• Proteinuria and hematuria are findings in glomerulonephritis.
• Types of glomerulonephritis progress through various disorders such as acute glomerulonephritis, chronic glomerulonephritis, nephrotic syndrome and renal failure.

Acute Poststreptococcal Glomerulonephritis (AGN)

• Acute Poststreptococcal Glomerulonephritis (AGN) results in a sudden onset of symptoms indicating damage to the glomerular membrane.
• Immune complexes deposit on glomerular membranes in Acute Poststreptococcal Glomerulonephritis (AGN).
• Symptoms result from damage to the glomerular membrane; edema, fever, fatigue, nausea, hypertension, oliguria, hematuria.
• Acute Poststreptococcal Glomerulonephritis (AGN) follows respiratory infections.
• Specific strains of group A streptococcus typically precede Acute Poststreptococcal Glomerulonephritis (AGN).
• Symptoms of Acute Poststreptococcal Glomerulonephritis (AGN) occur 1-4 weeks after pharynx or skin infection .
• Streptococci form immune complexes with corresponding antibodies and become deposited on glomerular membranes leading to Acute Poststreptococcal Glomerulonephritis (AGN).
• Acute Poststreptococcal Glomerulonephritis (AGN) affects all ages and is common in children 4-12 years old.
• Urinalysis will have hematuria, proteinuria, and oliguria.
• Red blood cell (RBC) casts and dysmorphic RBCs can be detected.
• Hyaline and granular casts and white blood cells in urinalysis.
• Elevated Serum antistreptolysin O titer (ASO) indicates the disease originated from streptococcal origin.
• Treatment includes managing hypertension, maintaining water and electrolyte balance, and understanding immune complexes will eventually clear blood.
• Permanent renal damage seldom occurs.

Rapidly Progressive Glomerulonephritis (RPGN)

• Rapidly Progressive Glomerulonephritis (RPGN) is a syndrome where damage to glomeruli is accompanied by rapid (within weeks to months) decline in renal function.
• Rapidly Progressive Glomerulonephritis (RPGN) can rapidly lead to renal failure.
• Increased risk of rapidly progressive glomerulonephritis is associated with systemic diseases, for example systemic lupus erythematosus.
• Deposition of immune complexes from systemic immune disorders on the glomerular membrane results in glomerulonephritis.
• Rapidly Progressive Glomerulonephritis (RPGN) is most common in people aged 40-60, and slightly more common in men.
• Urinalysis findings are initially similar to acute Glomerulonephritis (GN) but become more abnormal as disease progresses.
• Look for Markedly increased protein levels, macroscopic hematuria, and red blood cell casts in urinalysis.
• Low glomerular filtration rates (GFR) will be detected.
• GFR is the rate plasma ultrafiltrate is produced by glomeruli per unit of time.
• Treat with Immunosuppression such as Glucocorticoids & Cyclophosphamide AND Plasmapheresis to remove antibodies and immune complexes if necessary.

Chronic Glomerulonephritis

• Acute and other glomerular diseases can transition into chronic depending on the amount and duration of damage occurring to glomerulus.
• Chronic glomerulonephritis can lead to renal failure such as end stage renal disease.
• Etiology will show Marked decrease in renal function resulting from glomerular damage precipitated by other renal disorders.
• Chronic glomerulonephritis is subtle and progresses slowly until death, unless patient undergoes dialysis or renal transplant.
• Waxy and broad casts in urinalysis is a sign of chronic glomerulonephritis.
• Electrolyte imbalance is a characteristic of chronic glomerulonephritis.
• Treatment includes managing of precipitating condition and dialysis and transplant may be necessary.

Nephrotic Syndrome

• Nephrotic Syndrome can be caused by any of a group of diseases that damage the glomeruli and is not a disease itself
• Hallmarks of Nephrotic Syndrome is very high levels of protein in the urine and low levels of protein in the blood resulting In swelling, especially around the eyes, feet, and hands.
• Dysfunction of the membrane allow protein to pass through, depleting albumin, and causing increased lipid production.
• Usually a result of an underlying disease, and can occur as a complication of acute and chronic glomerulonephritis.
• Possibly secondary to systemic diseases; diabetes mellitus, systemic lupus erythematosus (SLE), infections and malignancy.
• Adult NS, Childhood NS with occurrences at any age with boys being affected more often.
• Can progress into renal failure.
• Hallmark is Massive proteinuria, low levels of serum albumin, high levels of serum lipids, and pronounced edema.
• Increased permeability of the glomerular membrane results in: Passage of proteins into urine where albumin is equal to proteinuria.
• Depletion of plasma albumin increases loss of fluid into the tissues, the effect of which is Edema and hypoalbuminemia.
• The liver will produce more lipids which means increased lipids in circulation, which in turn means one will see High cholesterol (lipidemia and lipiduria).
• Urinalysis findings will result in: Heavy proteinuria, microscopic hematuria, Renal tubular cells, Oval fat bodies, Fat droplets, and Fatty & waxy casts.
• Other significant tests include Elevated Cholesterol and triglycerides, Low serum albumin. Treatment focuses on identifying the underlying cause. Treatment may require treating NS through diet, medications, or both.

Tubular Disorders

• Tubular disorders affects the renal tubules in which tubular function is disrupted as a result of actual damage to the tubules
• Metabolic or hereditary disorder can potentially effect the functions of the tubules

Acute Tubular Necrosis

• Acute tubular necrosis (ATN) is characterized by the death of tubular cells with symptoms of an acute onset of renal dysfunction . It can be resolved when underlying cause is corrected.
• Acute Tubular Necrosis (ATN) can be due to Ischemic causes like damage to RTE cells produced by decreased blood flow or lack of oxygen presentation to the tubules a.k.a., ischemia.
• Acute Tubular Necrosis (ATN) can be caused by Toxic causes - presence of toxic substances in the urine filtrate.
• Causes of ischemic ATN include shock and trauma.
• Shock results in conditions decreasing blood flow throughout the body such as cardiac failures, sepsis, massive hemorrhage, or burns.
• Trauma results in crushing injuries or surgical procedures.
• Causes of toxic ATN include exposure to Aminoglycoside antibiotics, Antifungal agents, Radiographic dye, Ethylene glycol (antifreeze), Heavy metals and other poisons.
• Regardless, the mechanism is oxidative damage from ROS.
• Microscopic hematuria, Proteinuria, Renal tubular epithelial cells, Renal tubular epithelial cell casts are all elements of urinalysis of someone with acute tubular necrosis.
• Hallmark finding is detection by the presence of renal tubular epithelial cell casts in urinalysis.
• Hyaline, granular, waxy, broad casts in urinalysis is indicator.
• Other Laboratory Findings of someone with acute tubular necrosis will show elevated serum creatinine, BUN and Hyponatremia, hyperkalemia, hypocalcemia.

Fanconi’s syndrome

• Fanconi’s syndrome is an impairment in the proximal tubular function of the kidney which results in compounds that should be absorbed by bloodstream to be excreted in the urine.
• Compounds that may be lost in the urine include: glucose, amino acids, Phosphorus, sodium, potassium, bicarbonate, and water.
• There are two types, inherited and acquired; the latter includes exposure to toxic agents, heavy metals, prescribed drugs, and as a complication of multiple myeloma and renal transplant.
• Symptoms include excess amounts of glucose, amino acids, phosphorus, sodium, potassium and bicarbonate in urine.
• Results in other lab findings; glucosuria (due to excretion) can be detected with urinalysis .
• Treat underlying disease or the symptoms.

Diabetic Nephropathy

• Diabetic Nephropathy, Damage to the glomerular membrane,Glomerular basement membrane thickening.
• Increased proliferation of mesangial cells.
• Increased deposition of cellular and acellular material within glomerular matrix.
• Deposition associated with glycosylated proteins from poorly controlled diet. Results in sclerosis of vascular structure; therefore early microalbumin testing is crucial.

Non-Nephronic Disorders

Renal Interstitium

• The renal interstitium is the space between the nephron units.
• Interstitial cells are within the interstitium and are in close proximity to medullary blood vessels and tubule cells.
• Disorders affecting the interstitium can also affect renal tubules.

Introduction to Extranephric Disorders

• A UTI (urinary tract infection) is the most common of all renal diseases, affecting the urinary tract; the upper (renal tubules and interstitium) and the lower (urethra and bladder).
• Interstitial Inflammatory Disorders include Interstitial Nephritis and Interstitial Cystitis.

Lower Urinary Tract Infection.

• Cystitis is an infection of the bladder, and Urethritis is an infection of the urethra
• Symptoms include : Increased urine frequency and burning upon urination
• Urinalysis will show presence of pyuria and Bacturia
• Microscopic hematuria will be detected with mild proteinuria and increased pH
• Mild Leukocytosis is a sign.
• E. coli comprises 85% of Community-Acquired Cases.
• S. saphrophyticus is 10% with Wider variation in nosocomial cases like Klebsiella, Pseudomonas, Enterococcus, etc

Pyelonephritis (Upper UTI)

• Pyelonephritis (Upper UTI) is an infection of the renal tubules and interstitium that can be referred to as kidney infection.
• High fever, vomiting, radiating abdominal pain, and painful urination are symptoms.
• Upper UTI can be defined as chronic or acute with a high incident of structural abnormalities affecting a chronic UTI.
• An acute form have high rate of fatality (>40%) in elderly patients.

Acute Pyelonephritis

• Ascending movement of bacteria causes Acute Pyelonephritis
• Calculi, pregnancy, and reflux of urine from bladder to ureters can increase the risk for patients.
• Urinalysis is similar to cystitis with one exception being the presence of WBC casts.
• Other lab findings: Marked Leukocytosis (Neutrophilia) & Positive Urine Cultures.
• Causative Organisms: Similar to Lower UTI.

Chronic Pyelonephritis

• Kidney damage might occur from damage to tubules.
• Congenital structural defects causing reflux are the most common cause.
• Can affect emptying of collecting ducts and recurrent cycles of infection and inflammation cause scarring.
• Is most often diagnosed in children.
• Early urinalysis is similar to acute pyelonephritis though later one can find Granular, waxy, and broad casts; increased protein, hematuria, and renal concentration is decreased.

Acute Interstitial Nephritis (AIN)

• Acute Interstitial Nephritis (AIN) is rapidly developing inflammation that occurs within the interstitium.
• Allergic reaction to medications that reside in the renal interstitium can cause Acute Interstitial Nephritis (AIN).
• Symptoms include renal dysfunction, Fever and presence of skin rash
• Symptoms develop weeks after starting new medication. Ex; Penicillin, methicillin, ampicillin, cephalosporins, and sulfonamides.
• Urinalysis: Hematuria, Proteinuria, Pyuria, WBC casts and No bacteria (Sterile Pyuria).
• Staining for the presence of increased eosinophils may be useful to confirm diagnosis.
• Other Laboratory Findings: Eosinophilia in CBC, Hyperkalemia and Metabolic Acidosis.
• Discontinuation of medication and administration of steroids is treatment to use in order to control inflammation.

Renal Failure

• Renal failure comes in acute and chronic forms.
• Chronic Renal Failure often results from ongoing kidney issues causing steady damage to the kidneys; it is designated end stage renal disease.
• Decrease in the glomerular filtration rate with a steadily rising serum BUN are characteristics of end stage renal disease.
• Increased Blood urea nitrogen and kidney waste product in blood show kidney issues.
• Urinalysis: Proteinuria, Glycosuria and Granular, waxy, broad casts.

Acute Renal Failure

• Acute renal failure is a characterized by a sudden loss of renal function and is frequently reversible in occurrence.
• Decreased cardiac output, burns, surgery, hemorrhage and septicemia constitute is its causes.
• Renal diseases such as Acute glomerulonephritis, acute tubular necrosis, acute pyelonephritis and acute interstitial nephritis are the different types.
• In urinalysis, findings relate to the primary cause.

Renal Calculi (Nephrolithiasis)

• Renal Calculi is caused by hardened mineral deposits/kidney stone.
• Originates as microscopic particles developing into stones over time.
• Varies in size and forms in calyces and pelvis of the kidney, ureters and bladder.
• Waves of Excruciating Flank Pain (Renal Colic),Urinary Urgency & Nausea/Vomiting are key symptoms.
• Possible clumps of crystals in urine suggest a possible diagnosis (condition right for forming calculi) may be seen while there is no true indication on urinalysis.
• Hematuria is commonly identified while passing a stone.

Renal Calculi Formation

• Renal Calculi Formation occurs with changes in pH, chemical concentration where there is high level of calcium, oxalate or uric acid.
• Urinary stasis (ex: In dehydration) triggers this since there are high levels of substances do dissolve completely where crystals forms which slowly build into stones .
• Calcium stone is a common type of stone where there is too much Calcium phosphate, with High in take of calcium and/or oxalates which makes up 75-80% of stones.
• Magnesium ammonium phosphate (AKA Struvite Stones) results in 10% of stones and is is typically Associated with repeated UTIs.
• Uric acid results in 9% of stones in the kidneys which is Primarily in Gout
• Cystine results in 1% of cases and the stones are Only detected in Cystinuria.

Treatment to Reduce Stones

• Increase fluid intake in the body in order to help with urine output & the prevention of stones (diuretics), stone may dissolve.
• Small calculi (<5mm) can often be passed in urine
• Painful but treatable with with alpha-blockers.
• Larger stones must destroyed inside the body (lithotripsy) or surgically removed
• Extracorporal (outside the body), Uteroscopic, or Percutaneous will often use high-energy shock waves or lasers to break the structure of the stones.
• May require ureter stent placement

Metabolic Disorders

• Hundreds of specific enzymes are involved in human metabolism
• A genetic abnormality affecting the function of an enzyme or its production can lead to various metabolic disorders due to an inability for a substance to be broken down or there might be an inability for the production of essential substances.
• Classified by the particular building block that is affected. Disruption of metabolism results from inability to inherit gene/enzyme referred to as “inborn error of metabolism".
• Urinary overflow due to metabolic disturbances is usually result of abnormalities that trigger imbalances in the metabolic system.

Metabolic Disorders versus Renal Disorders

• Overflow is a disruption of a normal metabolic pathway which shows Increased plasma concentrations of the non-metabolized substances.
• Overflow Exceeds reabsorption ability of renal tubules - Inherited lack of specific enzyme for protein, fat, or carbohydrate metabolism which is known to be -inborn error of metabolism.
• Renal can be due to malfunctions in the tubular reabsorption mechanism.

Metabolic Disorders

• Can involve protein and carbohydrate metabolism where others exist.
• Commonly inherited and lead to intellectual disability; can use dietary restrictions to ease or prevent.
• These end products of body metabolism can be detected by additional screening tests (some routinely performed on all newborns).

Newborn Screening Tests

• There is a current state-mandated screening for as many as 31 inborn errors of metabolism (IEM).
• Heel stick blood tests are used for testing
• Testing is Performed before infant leaves hospital
• Has to occur over But >24 h due to the presence and detection of metabolites in blood.
• Tests Analyze by tandem mass spectrophotometry, MS/MS.

Amino Acid Disorders

• Phenylketonuria, Tryosyluria, Melanuria, Alkaptonuria, Maple syrup urine disease, Organic acidemias, Indicanuria, Cystinuria, and Cystinosis are all common urinary screening tests.

Phenylalanine-Tyrosine Disorders

• Consists of disorders that are major inherited disorders such as Phenylketouria (PKU) Tyrosyluria, and Alkaptonuria.

Phenylketonuria (PKU)

• Phenylketonuria (PKU) is a build-up of phenylalanine in the serum producing urinary overflow.
• Results from caused by missing or non-functional phenylalanine hydroxylase.
• The amino acid is Used in the breakdown of phenylalanine, but if the enzyme is not present breakdown cannot occur.
• Excess or build-up of phenylalanine leads to irreversible intellectual disability.
• Incidence is 1 in 10,000 to 20,000 births with management including elimination of consumption ofMeat, Eggs, Dairy, Soy, Nuts, Legumes, Artificial Sweeteners.
• Diagnosable with mousy odor to urine while the newborn has a required test (PKU Test).
• Blood test is the preferred route due to Initial screening not being part of urinalysis because increased blood levels of phenylalanine must occur prior to urinary excretion (which may take 2 – 6 weeks).
• Diagnosable with Bacterial inhibition test by the name of Guthrie.
• A heelstick is performed where the Blood is absorbed into filter paper circles.
• Blood impregnated disks are then placed on culture media streaked with the organism the strain known as, Bacillus subtilis. The observation of a growth around disk indicates the test is positive

Other Amino Acid Disorders

• Tyrosyluria (tyrosinemia) is a tyrosine aminotransferase or hydroxyphenylpyruvate dioxygenase defect.
• Results in excess of tyrosine in the plasma producing urinary overflow.

Alkaptonuria

• Is due to Defects the enzyme Homogetiate 1,2-dioxygenase which is Involved in breakdown of tyrosine and phenylalanine.
• Results in accumulation of homogentisic acid = black alkaline urine with liver & cardiac issues developing later in life.

Maple syrup urine disease

• Due to defects of Branched-Chain Alpha-Ketoacid Dehydrogenase; therefore, Inability to digest branched amino acids (Leucine, Isoleucine, Valine).
• Infants exhibit failure to thrive within 1 week as well as increased keto acids in the urine and a urine produces odor resembling maple syrup.

Cystine Disorders

• Cystinuria is defined as the genetic defect in amino acid transporter proteins .
• Increased cystine secretion through urine where Urine will smell of sulfur and patients are often asymptomatic unless stones form
• Cystinosis and Lysosomal Storage Disease are the categories where membrane transport protein for lysosomes are Defective in this disease as a result of Causes increased intracellular cystine accumulation. Causes increased intracellular cystine accumulation. Is Toxic in many tissues, Will also secrete cystine in urine resulting in crystals and sulfur odor.

Purine Disorders

• Lesch-Nyhan disease, inherited due to Inability to inherit gene sex-linked recessive due to Massive excretion of uric acid crystals.
• Motor defects, intellectual disability, and self-destruction such gout and renal calculi.
• Normal development only occurs 6 to 8 months which can result in the presence of Orange sand in diaper - Be alert for increased uric acid crystals in pediatric patients.

Other Metabolic Disorders

• There are over 65,000 families affected by Metabolic Diseases in the USA, as well as There are several hundred metabolic diseases examples include: Adreno- leukodystrophy - McArdle’s Disease Galactosuria, Niemann-Pick Disease, Gaucher, and Prader-Willi Syndrome.