Classifying Renal Diseases

Pre-renal:

Any process that decreases renal blood flow

Renal:

Glomerular disease:

Spectrum ranging from glomerulonephritis to nephrotic syndrome

Tubular-interstitial disease:

– Acute tubular necrosis (ATN):

o Ischemic

o Nephrotoxic insult

– Acute interstitial nephritis

Vascular disease:

– Vascular occlusion – renal artery/vein thrombosis, thrombotic microangiopathies (TTP, HUS, HSP)

– Intrarenal vasculitis – e.g. Wegener granulomatosis

Post-renal:

Any process that obstructs urine outflow

Urinary Tract Obstruction

Interference with urine flow within the urinary tract

Also known as “obstructive uropathy”

Etiology:

May be anatomic or functional obstruction, including:

– Compression by tumors

o E.g. kidneys, bladder, uterus, colon

– Compression by enlarged prostate, or prolapsed pelvic organ

– Pelvic adhesions (retroperitoneal fibrosis)

– Stones

– Strictures due to inflammation/scarring of walls

Sites of obstructions:

– Obstruction can occur anywhere in the pathway of urine flow

– Effects depend on the site, cause and degree of obstruction

Pathophysiology & Complications:

Dilation proximal to site of obstruction

– Hydronephrosis

o Dilation of renal pelvis & calyces

– Hydroureter

o Dilation of ureter

– Compensatory hypertrophy & urine accumulation

– Tubular and later glomerular damage if obstruction is not relieved

Clinical manifestations:

Difficulty to void, decreased urine output

Slowed stream, “dribble”

Urgency especially at night

False sense of fullness

Blood in the urine

Severity of manifestations will depend on:

– Location

– Degree

– Unilateral versus bilateral

– Upper versus lower urinary tract

– Duration and cause of obstruction

Kidney Stones

Masses of crystals, protein, or other substances that form within the kidney and may obstruct the urine flow

Etiology & risk factors:

Gender & race

Dietary pattern

Fluid intake

Geographic location; temp, humidity, rainfall

Seasonal factors

Occupation

Pathophysiology:

Salt supersaturation

Precipitation of a salt from liquid to solid state

Crystallization: growth from a nucleus into a stone

Factors affecting stone formation and crystallization:

– Temperature

– pH

– Organic material

– Influence of additional substances:

o Tamm-Horsfall protein (a crystal growth-inhibiting substance)

Classification of stones:

Calcium oxalates/phosphate are most common (70-80%)

Magnesium/ammonium phosphate

Uric acid stones

Stones < 5mm will likely be excreted via urine, while those > 1cm will not

Clinical manifestations & Diagnosis

Renal colic:

– Moderate to severe spasms of pain originating in flank, radiating to groin

May have associated nausea, vomiting

Urinary urgency and frequency

Diagnostic testing includes:

– Urine analysis

o Hematuria is an indicator of stones

– Imaging (x-ray, ultrasound, and/or computed tomography)

o Kidney, ureter, bladder

Neurogenic Bladder

Bladder dysfunction caused by neurogenic disorders (brain, spinal cord, peripheral nerve) interfering with micturition

Etiology:

Multiple of neurologic disorders including:

– Parkinson’s disease

– Multiple sclerosis (MS)

– Infection of the brain or spinal cord

– CVA

– Peripheral neuropathies

– Pelvic surgery

– Congenital (I.e. spina bifida)

Pathophysiology:

Lesions in brain centers or the spinal cord

Upper or lower motor neuron lesions impacting the ability to control micturition thus leading to overactive or underactive bladder syndrome

Clinical manifestations:

Frequency, urgency, nocturia

Retention with overflow

Stress incontinence

Renal Tumors- Renal Cell Carcinoma

Malignant tumor (adenocarcinoma) originating from tubular epithelium

Most common in males > 60 years

25% present with metastasis, including to lung, liver, bone, and lymph nodes

Clinical manifestations:

Usually presents in advanced cases

Dull aching flank pain

Mass

Hematuria

Renal Tumors- Wilm’s Tumor

A common childhood cancer

– Prevalence in children 2-4 years old

Mostly unilateral

Clinical Presentation:

– Abdominal swelling/ mass

– Pain

– Hematuria

Urinary Tract Infection (UTI)

Inflammation of urinary epithelium mostly due to infection

Most common pathogen:

– Escherichia coli

Lower UTI (cystitis/urethritis):

– Inflammation of the bladder (cystitis) and/or urethra (urethritis)

Clinical manifestations:

– Frequency

– Dysuria

– Urgency

– Lower abdominal and/or suprapubic pain

Upper UTI (pyelonephritis):

– Infection of kidney and renal pelvis

Risk/ predisposing factors:

– Vesicoureteral reflux

– Urinary tract obstruction

– Previous pyelonephritis

– Immunocompromised state

Common pathogens:

– E. coli, Proteus, Pseudomonas

Pathophysiology:

o Ascending infection from lower UTI

o Persistent or recurring episodes of acute pyelonephritis

o Scarring, further kidney damage & renal failure

Additional considerations

– What is the overall clinical condition or associated comorbidity?

– Is a lab diagnosis available?

– Is the person pregnant and are there complications?

Glomerulonephritis

Inflammation/damage of the glomeruli

Etiology/Forms:

Immune injury (most common):

– Post-streptococcal glomerulonephritis:

o Most common cause of hematuria in children

o Several weeks following infection with group A Streptococci

o Immune complex deposition in glomeruli (Type III hypersensitivity)

– IgA nephropathy (Berger’s disease):

o A common cause/type of glomerulonephritis world wide

o Common between late teens and late 30s and runs in families

o IgA deposition in glomeruli (Type II hypersensitivity)

– Good Pasture syndrome:

o Develops one week following upper respiratory tract infection (URTI)

o Pathological Triad:

1. Anti-GBM antibodies

2. Rapidly progressive glomerulonephritis

3. Pulmonary hemorrhage

Non-immune injury:

– Drugs

– Toxins

– Ischemia

o Vasculitis (E.g. Wegener granulomatosis)

Secondary to systemic diseases:

– SLE (Lupus nephritis)

– DM (Kimmelstiel–Wilson nodules is a histopathological finding)

– Amyloid

– HTN

Pathophysiology:

Glomerular inflammation (review pathology of inflammation)

Rapidly progressive

Clinical manifestations:

Hematuria with red cell casts

Edema

Oliguria

Hypertension

Low grade fever, flank pain

Diagnosis

Clinical presentation

Renal biopsy (invasive technique) but confirms pathological form and guides treatment

Complications:

Can proceed to nephrotic syndrome

Nephrotic Syndrome

A syndrome whereby a glomerular lesion leads to massive protein loss

Etiology:

Diabetes mellitus and hypertension are the most common causes for nephrotic syndrome

Glomerulonephritis

Others:

– Amyloidosis

– Cancer

– Drugs

– SLE

– HIV

Types (histo-pathophysiological):

Minimal change disease

– Mainly children, NSAIDs

Membranous glomerulonephritis

– Adults, NSAIDs, cancer

Focal segmental glomerulosclerosis

– HIV patients

Pathophysiology and clinical manifestations:

Glomerular injury that leads to protein leakage

Proteinuria: ≥3.5 g of protein in urine/ day

Hypoalbuminemia: <3 gm/dL

Edema

– May be periorbital, generalized and/or pitting

Hyperlipidemia, lipiduria

– Hyperlipidemia occurs from decreased protein levels

– Proteins are required in the form of lipoproteins for the uptake of lipids into tissue

– Absence of proteins leads to build-up of lipids in the blood

Hypogammaglobulinemia

Vitamin D deficiency

Hypercoagulable state

Manifestations of RAAS stimulation

Acute Kidney Injury (AKI)

Sudden decline of kidney function

– Occurs on a spectrum ranging from minimal changes in kidney function to kidney failure requiring dialysis and kidney transplant

Failure of kidney function means:

– Reduction of glomerular filtration and creatinine clearance →

– Accumulation of nitrogenous waste in blood →

– Encephalopathy and impairment of brain function (uremia and high creatinine).

Stages of AKI:

Renal insufficiency:

– Decline kidney functions by 25% of normal (GFR~ 25-30mL/min)

– Mild elevation of serum creatinine

Renal failure:

– Significant loss of kidney function, requiring dialysis

End stage renal failure (ESRF; uremia):

– Renal function is less than 10%, requiring dialysis

Etiology & pathophysiology:

AKI can originate from causes before (pre-renal), within (intrarenal), or after (post-renal) the kidney

Pre-renal causes are occurred before the kidney and are due to impaired renal perfusion

– The most common causes for AKI, including:

o Hypovolemia:

1. Hemorrhage (E.g. trauma, GI bleeding, childbirth)

2. Loss of plasma volume (E.g. Burns)

3. Loss of water/electrolytes (E.g. Severe vomiting, diarrhea, intestinal obstruction, diuretic overuse)

o Hypotension/ Systemic vasodilation (E.g. Shock, CHF, massive pulmonary embolism)

o Cirrhosis through the process of ↓ albumin → ↓ colloid oncotic pressure → ↓ intravascular volume

Intra-renal: Causes from within the kidney and include renal parenchymal and interstitial disorders

– Acute tubular necrosis (ATN) is the most common

o Causes for ATN include:

1. Ischemic: E.g. Post-operative ischemia, sepsis

2. Toxic: E.g. Drugs, antibiotics eg gentamicin

3. Crystals/pigments: E.g. Uric acid, oxalates, myoglobin, hemoglobin

Post-renal: AKI originating after the kidney, and the most rare

– Obstructive uropathy: E.g. Enlarged prostate, bladder stones, uretheral, ureteric (bilateral)

Clinical manifestations:

– Oliguria in various levels

– Manifestation of underlying pathology

Pathogenesis & Stages:

1. Initiation phase (first 36h)

– Kidney injury is evolving with slight decrease in urine output and increase in blood urea nitrogen (BUN)

– Prevention of injury is possible

2. Maintenance phase

– Established kidney injury and dysfunction

– Sustained oliguria (40-400mL/day)

– Increase in ECF volume → can be associated with edema, pulmonary congestion

– Hyperkalemia may be present leading to EKG changes and increased risk of sudden death

– Metabolic acidosis

3. Recovery phase (2-3 weeks)

– Brisk diuresis (up to 3L/day) leading to urinary loss of electrolytes Ca, K, PO4

– Hypokalemia (one of most serious complications of recovery) leading to EKG changes and presenting a risk for cardiac arrhythmias

– Renal function eventually recovers with BUN and serum creatinine returning to baseline

Chronic Kidney Disease (CKD)

Chronic progressive loss of renal function

CKD is defined as glomerular filtration rate (GFR) < 60 mL/ min/1.73 m2, for 3 months or more irrespective of cause

Etiology:

Systemic diseases:

– E.g. Hypertension and Diabetes mellitus

Intrinsic kidney disease:

– Glomerular or tubular

– Glomerulonephritis

– Pyelonephritis

– Obstructive uropathy

Stages:

Normal Kidney Function: GFR >90mL/min

Mild: GFR 60-89mL/min

Moderate: GFR 30-59mL/min

Severe: GFR 15-29mL/min

End stage: GFR <15mL/min (regular dialysis or transplantation)

Pathophysiology:

Continued loss of functioning nephrons

Glomerular hypertrophy and adaptive hyperfiltration

Proteinuria and glomerulosclerosis

RAAS activation and increased Angiotensin II leading to glomerular and systemic hypertension

Erythropoietin deficiency

Kidney unable to excrete potassium (K), Phosphate (PO4), Magnesium (Mg)

Tubulointerstitial inflammation and fibrosis

Clinical manifestations:

Manifestations of uremia

All systems are affected:

– Reduced GFR, increased plasma creatinine, BUN

– Increased sodium and water retention leading to edema and hypertension

– Metabolic acidosis when GFR 30-40%

– Bone change and subsequent fractures

– Proteinuria and impaired fat and carbohydrate metabolism

– Hypertension, CHF, edema

– Pulmonary edema, Kussmaul respiration

– Anemia, hypercoagulability & bleeding

– Increased risk of infection

– Uremic encephalopathy

– Peripheral neuropathy

– Impaired sexual/reproductive functions (anovulation, erectile dysfunction)

– Pruritus, sallow skin color

Thrombotic microangiopathies

Vascular kidney lesions where thrombosis is common

Characterized by a “ thrombotic” triad of symptoms:

1. Thrombocytopenia & Purpura

2. Hemolytic anemia

3. Renal damage / failure

A common cause of acute renal failure

Two common conditions, each exhibit additional different pathologies:

1. Hemolytic Uremic Syndrome

2. Thrombotic Thrombocytopenic

Hemolytic-Uremic Syndrome (HUS)

Etiology:

– Infections

i. Bacterial:

• E coli; O:157 H:7

• Shiga toxins (secreted by this E coli strain; names after Shigella shiga toxin as it has similar effect) causing damage to the blood vessel (endothelium/RBCs)

ii. Viral infection

Pathophysiology

– Thrombotic Triad

– Glomerular damage

o Cell swelling

o Blood vessel occlusion with fibrin clots

– Acute hemolytic anemia (schistocytes seen in peripheral blood smear)

– Splenomegaly

– Thrombi in microcirculation including renal vasculature

Clinical manifestations

– Sudden onset of pallor, bruising or purpura, irritability, and oliguria

– Slight fever

– Anorexia

– Vomiting

– Diarrhea

o Stool is watery and blood stained

– Abdominal pain, mild jaundice (due to hemolysis)

– Renal failure is apparent within the first few days, causing:

o Metabolic acidosis

o Hyperkalemia

o Hypertension

Thrombotic Thrombocytopenic Purpura (TTP)

Etiology & Pathophysiology:

– Thrombotic Triad

– Deficiency in ADAMTS13 enzyme

o ADAMTS13 is responsible for cleavage of large multimers of VWF (von Willebrand factor) protein

o VWF is protein, which has two critical

roles in coagulation cascade and clot formation at the site of injury

• VWF is a sticky multimeric protein which binds platelet and injured subendothelium to create thrombus at site of injury.

o VWF is a carrier for FVIII and protects it from proteolytic cleavage

o The deficiency in ADAMTS13 enzyme → elevated levels of VWF large multimers → thrombosis

– Genetic mutations

Clinical manifestations:

– Differentiating features from HUS would be neurologic complications:

o Recurrent symptomatic episodes including seizures and vision loss

– Lab features:

o Serum ADMTS 13

o Serum VWF

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