Pathophysiology of

renal desaeses
 The most important for renal function
is GLOMERULAR FILTRATION
occuring in glomeruli.

 Sufficient GFR is required to excrete

waste products.

 Filtration is driven by the effective

filtration pressure.

 Single-nephron-GFR is carefully
adjusted by tubuloglomerular
feedback.
5
Tubulo-glomerular feedback
Tubular Na+ load reaching DCT

decreased
increased
Na+ K+ Cl- H2O

Na+ K+ Cl- H2O

K+

Macula densa cell

Na+
PGE2, NO
K+

Granular cells of the afferent arteriole

Na+
Adenosine
Renin → AngI → AngII
SMC of aferent art..
SMC of efferent art..
costriction → ↑ glom. capillary costriction → ↓ glom. capillary
pressure → ↑ snGFR pressure → ↓ snGFR
Hyperglycaemia → glucosuria → Na+ dilution at DCT → Renin/AngII → hyperfiltration

Glukoza stanowi
dodatkowy osmolit
zwiększający
zawartość H2O -
„rozcieńczenie” Na+
Elevated tubular glucose
exceeds tubular transport
6
maximum
Mechanisms of GFR reduction
8

The volume of urine depends on both filtration and tubular reabsorption.

Anuria = No filtration!
Polyuria = poor reabsorption (filtration can be proper or diminished)!
 Common Manifestations of Kidney Disease

Pain
 Renal pain: nephralgia

 Generally felt at costovertebral

angle;
 Due to distention/inflammation

of the renal capsule; has a dull,

constant character
 Pain transmitted to T10 - L1 by
sympathetic afferent neurons; may
be felt throughout dermatomes
(area of skin innervated by a
specific spinal cord segment)
Common Manifestations of Kidney Disease (Cont.)

Abnormal Urinalysis Findings

 Provides a foundation for the differential
diagnosis of renal dysfunction
 Dipstick and microscopic urinalysis results
provide clues to intrarenal pathologies
 Color
➢ Dark, strong-smelling urine: decreased renal function
➢ Cloudy pungent urine: infectious process
Urinalysis Urine sediment: cells, bacteria,
crystals, tubular casts
Common Manifestations of Kidney Disease (Cont.)

Other Diagnostic Tests

 Kidney/Ureter/Bladder x-ray identifies gross

abnormalities related to size, position, and shape

(may show renal calculi)
 Renogram/renal scan shows renal vasculature and

tumors
 Ultrasonography differentiates tissue characteristics

– easy, rapid, available, no side-effects

 CT/MRI used to provide detailed information about

the vasculature and tissue

 Infection of the urinary tracts
 Normal protective mechanisms against
infection
➢ Acidic pH
➢ Presence of urea in the urine
➢ Men: bacteriostatic prostatic secretions
➢ Women: glands in the distal urethra secrete
mucous
➢ Micturation: wash out pathogens
➢ Unidirectional urine flow: prevents reflux
 Infection (Cont.)
 Infection of renal
pelvis/parenchyma
(pyelonephritis) via the
bloodstream (hematogenous
spread) or, much more
commonly, via ascending
infection from the bladder.
 Lower UT infections
 Primary symptoms are local discomfort on
urination (dysuria) and urinary frequency
and urgency; signs of systemic infection
are absent.
 Examination of the urine sediment typically
shows bacteria and white cells (pyuria).
White cell casts are not seen, since there
is no involvement of the kidney.
 Infection (Cont.)
Acute Pyelonephritis
 Major risk factor: pregnancy

 Clinical manifestations:
➢ CVA tenderness (classic sign)
➢ fever,
➢ chills,
➢ N/V,
➢ anorexia
 Infection (Cont.)
Acute Pyelonephritis
 May lead to urosepsis: spreading of bacteria into

the bloodstream originating from a UTI

 Diagnosis: presence of WBC casts indicative of

upper UTI, nitrite in urine
 Infection (Cont.)
Chronic Pyelonephritis
 Can result in chronic kidney

disease
 Usually associated with reflux or
obstructive process leading to
persistent urine stasis
 Chronic inflammation causes

scarring and loss of functional

nephrons
 Nephrolithiasis
Renal Stones (Renal Calculi)
 Crystal aggregates composed of organic and inorganic materials
located within the urinary tract
 Stones may form because the urine becomes too saturated
with salts that can form stones or because the urine lacks the
normal inhibitors of stone formation.
 Urinary supersaturation: essential requirement for stone formation
 Most stones contain calcium (oxalate or phosphate); others
include uric acid, struvite, cystine, and stones associated with
certain medications
Cystine TH protein
Osteopontin
Litostatin
Prothrombin fragment 1
Inter alpha inhibitor
 Hypercalciuria

Stone
Pathophysiology Clinical clues
Cause composition

Urine calcium
Absorptive hypercalciuria Increased absorption in gut concentrations >6 mmol/L
(240 mg) per day
Increased absorption in gut and High concentrations of
Hyperparathyroidism
bone release parathyroid hormone
High concentrations of
Immobilisation Bone resorption
vitamin D

Sodium-induced physiological renal Urine sodium

Excess of sodium in diet calcium leak. Possible component concentrations >200
of gut hyperabsorption mmol/L per day
Calcium oxalate
or phosphate Urine ammonium iron
concentrations high
Urine sulphate
Excess of protein or acid in Protein-induced bone loss and concentrations high
diet renal leak. Urine pH low
Urine citrate
concentrations <1·7
mmol/L per day
Bone loss, gut hyperabsorption,
Range of monogenic
and renal leak in various
disorders
combinations
Low osmolarity

High osmolarity
Struvite stones
 Obstruction of UT

 Obstructive processes cause

➢ Urine stasis
• Predisposes to infection and
structural kidney damage
 Common causes
➢ Stones: most common
➢ Tumors
➢ Prostatic hypertrophy
➢ Strictures of the ureters or urethra
 Obstruction (Cont.)
 Complete obstruction
consequences:
➢ Hydronephrosis
➢ Decreased GFR
➢ Ischemic kidney damage because
of increased intraluminal pressure
➢ Acute tubular necrosis (intrarenal
acute renal failure)
➢ Chronic kidney disease
 Glomerular Disorders
 Also called glomerulopathies
 Alter glomerular capillary structure and
function
 Glomerular Disorders (Cont.)
 Morphological classifications:

➢ Diffuse (all glomeruli)

➢ Focal (some but not all glomeruli)

➢ Global (affecting all parts of the glomerulus)

➢ Segmental (only specific parts/patches of the
glomerulus)

➢ Membranous (thickening of glomerular capillary walls)

➢ Proliferative
➢ Sclerotic (scarring)
 Glomerular Disorders (Cont.)
 Classifications
➢ Primary:only the kidney is involved, has
immune-related background with
inflammation affecting the glomeruli

➢ Secondary: results from other diseases,

conditions, medications
• Goodpasture syndrome
• Systemic lupus erythematosus
• Diabetic nephropathy
 Glomerular Disorders (Cont.)

 All primary and most secondary glomerular diseases are

characterized by the formation of immune complexes that
contain immunoglobulins and complement components.

 Immune deposits form in the glomerulus either actively

because the target antigen(s) is localized predominantly in the
glomerulus or, less commonly, passively because of the role
of the glomerulus in filtration.
 Glomerular Disorders (Cont.)
 Antibodies that induce glomerular immune deposits may be directed
against:
➢ Normal constituents of the glomerulus (for example M-type phospholipase A2
receptor in idiopathic membraneous nephropathy or alpha-3 chain of type IV collagen in
Goodpasture syndrome)
➢ Nonrenal self-antigens, that localize in glomeruli because of passive trapping often via
spontaneous aggregation or by interaction with negatively charged sites on the
glomerular capillary wall (for example abnormally glycosylated IgA in IgA nephropathy or
DNA nucleosome complexes in lupus nephritis)
➢ Exogenous antigens or immune aggregates that localize in glomerular capillaries via
charge affinity for glomerular structures, passive trapping, or local precipitation of
macromolecular aggregates (for example HCV antigen-containing cryoglobulins in
hepatitis C virus-associated membranoproliferative GN)
 Glomerular Disorders (Cont.)
Acute Glomerulonephritis
 Clinical manifestations
➢ Proteinuria, oliguria and azotemia, edema and hypertension

 Underlying mechanisms:
➢ Attraction of immune cells to the area of inflammation results in lysosomal
degradation of the basement membrane, dysfunction of podocytes, which
leads to proteins leak and eventually (depending on severity of
destruction) blood cells
➢ Reduction of GFR:
• contraction of mesangial cells resulting in decreased surface area for filtration
• proliferation of endothelial cells, mesangial cells, epithelial cells (they may obstruct
glomerular capillaries or compress the glomeruli)
 Glomerular Disorders examples
Acute Glomerulonephritis
 Postinfectious acute glomerulonephritis
➢ Follows streptococcal throat / skin
infections
➢ Usually in developing countries
➢ Common in children

Mechanisms:
➢ streptococcal neuraminidase alters host’s IgG →IgG/anti-IgG
immune complexes are formed and then collect in the glomeruli.
➢ antobodies against antistreptolysin O, hyaluronidase, DNAase-B,
and streptokinase are also found
 Glomerular Disorders examples
Acute Glomerulonephritis
 IgA nephropathy (Berger’s
disease)
➢ Most commonly diagnosed
➢ Common in adults
➢ After upper respiratory or
gastrointestinal infections
➢ Hematuria presents in 1 to 2 days
➢ Prognosis: variable, may progress
to end-stage renal disease
 Glomerular Disorders examples
Crescentic Glomerulonephritis
 Describes the morphology of rapidly
progressive glomerulonephritis (RPGN)
 Lesions are crescent shaped
 Causes
➢ Complication of an acute or subacute infection
or multisystem disease; drug exposure; primary
disorder (absence of systemic disease)
 Acute onset, with hematuria, proteinuria, and
red cell casts followed by a swift decline in
renal function within 6 months
 Glomerular Disorders (Cont.)
Goodpasture Syndrome - example of RPGN
 Autoimmune disorder, anti-GBM antibodies
 Combination of glomerulonephritis with alveolar
hemorrhage, anti-glomerular basement membrane
antibodies
 Shortness of breath and hemoptysis
 Glomerular Disorders (Cont.)

Chronic Glomerulonephritis
 Progressive course ultimately developing into end-stage
renal disease due to glomerular sclerosis and loss and fibrosis of
the kidney

 Present with persistent proteinuria, with or without

hematuria, and slowly declining renal function
 Supportive interventions throughout course of disease
 Dialysis or kidney transplantation necessary
 Glomerular Disorders (Cont.)

 Clinical types (based on protein and

manifestations)
➢ Nephrotic syndrome is specifically
characterized by huge protein loss ≥3 to 3.5
grams in 24 hours

➢ Nephritic syndrome is also a reflection of

glomerular inflammation
• Mild to moderate proteinuria
• Hematuria and RBC casts present in sediment
GFR
 Nephrotic Syndrome
 Occurs due to increased glomerular permeability to proteins
 Urinary loss of >3.5 g of protein per day (unbalanced protein
loss) → Proteinuria leads to hypoalbuminemia → decreased
blood colloid osmotic pressure → generalized edema;
 Increase in liver activity can cause hyperlipidemia and
hypercoagulability
 Lipoproteins are lost with urine - lipiduria
 Infections: loss of Ig, transferin, ceruloplasmin
Nephrotic Syndrome
 Overhydration in nephrotic syndrome

 Patients with the nephrotic syndrome have hypoalbuminemia and

profoundly decreased plasma oncotic pressures because of the loss of
serum proteins in the urine.
 In majority of cases this leads to intravascular volume depletion
(„intravascular underfill”) and activation of the renin-angiotensin-
aldosterone system and the sympathetic nervous system. Vasopressin
secretion is also increased. Such patients also have altered renal
responses to atrial natriuretic peptide. All above lead to overhydration.
Despite signs of volume overload such as edema or anasarca, patients
may develop signs of intravascular volume depletion, including
syncope, shock, and acute kidney injury.
 IN the minority of patients with the nephrotic syndrome (usually in
those with less pronounced hypoalbuminemia) there is no hypovolemia
and tendency to hypotension but they also tend to develop
overhydration (they are „overfilled”) due to increased renal Na+ and
water reabsorption even without excessive RAA activation.
 Mechanisms of edema in neprhotic syndrome

„Overfill” hypothesis

„Underfill” hypothesis
 The mechanism of excessive primary renal Na+ (and
water) retention in „overfill theory”

Na/K ATPase
Na+

H2O

Plasminogen filtered by the nephrotic glomeruli is converted to plasmin by

urokinase-type plasminogen activator in the cortical collecting duct cells. Plasmin
then proteolytically removes the γ inhibitory domain from epithelial sodium channel
(ENaC), resulting in near full activation of ENaC.
Excessive Na+ reabsorbtion leads to water retention.
 Hypercoagulability in nephrotic syndrome

 Hypercoagulability is caused by
renal losses of proteins C and S
and antithrombin, as well as
elevated serum fibrinogen and
lipid levels due their hepatic
overproduction.

 Immobilization from a prolonged

hospital stay puts this patient at
additional risk for deep venous
thrombosis.
Minimal Change Disease (MCD) – typical cause
of nephrotic syndrome

 Previously called lipoid nephrosis

 Alteration in glomerular podocytes, whereby

the foot processes fuse together.

 The pathologic changes are most evident on

electron microscopy, which reveals obliteration
of epithelial foot processes and slit diaphragm
disruption. As perfusion of glomeruli is
unaffected the filtration is not significantly
affected → daily urine contains large amounts of
proteins.
 Sudden onset of edema, nephrotic levels of protein loss, and
hypoalbuminemia
Renal consequences of proteinuria
 Nephritic Syndrome

due to overhydration resulting from oliguria

Hypertension due to overhydration and RAA overactivation
5

Renal tubular acidosis

Distal

Type 1. Decreased H+ excretion

Proximal

Type 2.
Decreased Type 4. ↓ response
HCO3- to aldosterone
reabsorption
 Renal failure
The term renal failure (or renal insufficiency) is generally applied
to an impairment in the GFR.
Decreased GFR leads to excretory failure and gradual retention
of a number of substances, some of which are routinely
measured (such as BUN and plasma creatinine).

Acute Chronic

Acute kidney injury Chronic Kidney Disease

 Acute Kidney Injury
 Sudden reduction of kidney function
causing
➢ Disruptions in fluid, electrolyte, and acid-base
balances
➢ Retention of nitrogenous waste products
➢ Increased serum creatinine
➢ Decreased glomerular filtration rate (GFR)
Severity of AKI
Creatinine/GFR relationship
 Acute Kidney Injury

Etiology and Pathophysiology

 Abrupt reduction in renal excretory

function producing an accumulation of

waste materials in the blood

 May be due to aging and associated

comorbidities, or due to insults to the
kidney
 Acute Kidney Injury

Prerenal Kidney Injury

 Due to conditions that diminish perfusion

of the kidney
➢ Hypovolemia, hypotension, heart failure
➢ Renal artery obstruction
➢ Fever, vomiting, diarrhea
➢ Burns
➢ Overuse of diuretics
➢ Edema, ascites
➢ Drugs: ACE inhibitors, angiotensin II blockers,
NSAIDs
 Acute Kidney Injury

Prerenal Kidney Injury

 Characterized by low GFR, oliguria, high

urine specific gravity and osmolality,

and low urine sodium

 Prolonged prerenal ARF leads to acute

tubular necrosis (intrinsic, renal AKI)
 Acute Kidney Injury

Postrenal Kidney Injury

 Due to obstruction within the urinary collecting system
distal to the kidney; elevated pressure in Bowman
capsule; impedes glomerular filtration
 Clinical findings based on duration of the obstruction
 Prolonged postrenal ARF leads to acute tubular
necrosis (intrinsic AKI) and - if continues - leads to
irreversible kidney damage
 Acute Kidney Injury

Intrinsic/Intrarenal Kidney Injury

 Due to a primary dysfunction of the nephrons and the

kidney itself

 Most common problem within the renal tubules

resulting in acute tubular necrosis (ATN);
➢ ATN etiology:
• Nephrotoxic insult (for example contrast media)
• Ischemic insults (shock, sepsis)

 Intrinsic AKI may also occur with glomerular, vascular,

or interstitial etiologies.
 Acute Kidney Injury (Cont.)
Intrinsic/Intrarenal Kidney Injury
 2 pathophysiological processes
➢ Vascular: renal blood flow decreased;
hypoxia, vasoconstriction
➢ Tubular: inflammation and reperfusion injury,
causes casts, obstructs urine flow, tubular
backleak

 Can repair itself or if injury is sustained

leads to end-stage renal disease
Acute Tubular Necrosis
 Acute Kidney Injury

Clinical Presentation of Acute Tubular Necrosis

 Divided into three phases
➢ Prodromal
➢ Oliguric
➢ Post-oliguric

 Clinical presentation varies with the phase

 Acute Kidney Injury (Cont.)
Prodromal (initial) Phase
 Normal or declining (in > 50% pts) urine output
 Serum BUN and creatinine begin to rise
 Insult to the kidney has occurred and the duration of this
phase will vary depending on
➢ Cause of the injury:
• Amount of the toxin ingested
• Duration and severity of the hypotension
 Acute Kidney Injury (Cont.)
Oliguric Phase
 May last up to 8 weeks with urine output 50-400 mL/day
 Characterized by oliguria and progressive uremia;
decreased GFR;
➢ signs/symptoms of fluid excess, hyperkalemia, uremic
syndrome, acidosis,
 Typically may last 1 to 2 weeks
 Dialysis may be required
 Acute Kidney Injury (Cont.)
Post-oliguric (polyuric) Phase
 Termination of oliguric phase represents renal recovery
 Urine volume increases (diuresis); tubular function is
impaired and azotemia continues
 Fluid volume deficit until kidneys recover
 May last 2 to 10 days; full recovery 1 year
➢ Full recovery: creatinine and BUN normal
➢ Usually some degree of renal insufficiency persists
Stages of ATN - summary
Chronic Kidney Disease
 Chronic Kidney Disease
 Outcome of progressive and irrevocable loss of
functional nephrons and reduction of GFR

 Progressive process:
➢ Chronic kidney disease (CKD) → Chronic renal failure
(CRF) → End-stage renal disease (ESRD)

 A global health problem often linked with other

comorbidities, primarily hypertension and
diabetes mellitus
 Chronic Kidney Disease
 Clinical definition:

➢ Defined as decreased kidney function or

kidney damage of 3 months’ duration
based on blood tests, urinalysis, and
imaging studies

➢ Also defined as GFR <60 ml/minute/1.73

m2 for 3 months with or without indication
of damage to the kidney
Chronic Kidney Disease (Cont.)
Risk Factors
 Diabetes

 Hypertension
 Recurrent pyelonephritis
 Glomerulonephritis
 Polycystic kidney disease
 Family history of CKD

 History of exposure to toxins

 Age over 65
 Ethnicity
Pathophysiology of Progression of
Chronic Kidney Disease

 Progressive and irreversible

 GFR reduction occurs with nephron loss
➢ Kidneys compensate until ~75% of nephrons are
damaged/non-functional

 Stages of chronic kidney disease

➢ Progression monitored by a staging system
• Based on increasing severity of disease
➢ Five stages of progression and with each higher stage the
GFR and kidney function declines
 Stages of Chronic Kidney Disease

 Stages are based on GFR:

➢ In stage 1 (GFR <90) and stage 2 (GFR 90-60) – no
significant consequences, excretory function preserved
➢ By stage 3 (GFR 30-59): symptoms may be starting to
appear and treatment may be needed
➢ In stage 4 (GFR: ~15-29): symptoms + complications
present
➢ In stage 5 (GFR <15): end-stage renal failure -renal
replacement therapy needed or death will ensue
Adaptation to decreased neprhon number

With decreasing
nephron number, the
remaining increase
the filtration (to
sustain global GRF)
and become more
susceptible for
further injury
Pathophysiology of Progression of
Chronic Kidney Disease
Complications of Chronic Kidney Disease

 Hypertension and cardiovascular disease

➢ Hypervolemia, escalated atherosclerotic
process, heightened RAAS and SNS activity
 Uremic syndrome
➢ Retention of metabolic wastes; impaired
healing, pruritus; dermatitis, uremic frost
 Metabolic acidosis
➢ Retention of acidic waste products;
hyperkalemia; kidneys lose ability to excrete H+
ions and produce bicarbonate
Complications of Chronic Kidney Disease

 Electrolyte imbalances
➢ Retained potassium, phosphorus, magnesium

 Bone and mineral disorders

➢  phosphorus (due to its low excretion) binds Ca++ → hypocalcemia
(promoted by low intestinal absorption due to lack of vit. D3) →
PTH → osteolysis (Ca and P release) – vicious circle

 Malnutrition
➢ Decreased intake from uremic syndrome, depression, dietary
limitations, changes in taste, protein-energy wasting; negative
nitrogen balance
Complications of Chronic Kidney Disease

 Anemia
➢ Lack of erythropoietin; uremia shortens RBCs
life; combination of worsening CKD, anemia,
and heart failure (cardiorenal anemia
syndrome)
 Pain
➢ Many reasons; disease itself, treatment,
comorbidities
 Depression
➢ Co-morbid conditions; disease itself; disruption
of social interactions and relationships
 Metabolic changes vs GFR in CKD

Stage:
Renal disese 18 0%
Mild Moderate Severe ESRF
with normal GFR
16,6

14,6

Acidosis
12,6
12
Creatinine level

Hyperkalemia

Nephrons
10,6
Malnutrition
8,6
Anaemia

6,6 Disturbed Ca – Pi balance

6
Dyslipidemia
4,6
Arterial hypertension 4
3
2,6
Disturbed urine concentration 2
1,5
0,6 0,6 0,6 0,6 0,6 0,7 0,9 100%
120 110 100 90 80 70 60 50 40 30 20 10 0

GFR

124
Time – months/years
Cardio-renal syndrome
 Congenital Abnormalities
Cystic Kidney Diseases
 Genetically transmitted renal disorder resulting in

fluid-filled cysts that can expand and disrupt urine

formation and flow; may be localized to one area or
affect both kidneys
 Can lead to renal failure, requiring dialysis or

transplantation
 2 types
➢ Autosomal recessive forms
➢ Autosomal dominant types
Congenital Abnormalities (Cont.)
Normal vs Polycystic Kidneys
 Congenital Abnormalities (Cont.)

Cystic Kidney Diseases

 Autosomal recessive forms
➢ Evident at birth
➢ Kidneys enlarged
➢ Respiratory distress or
palpable kidneys on physical examination
➢ Severe systemic hypertension
➢ Liver problems
➢ Chromosome 6p
➢ Diagnosis: inheritance pattern with liver biopsy
Congenital Abnormalities (Cont.)
Cystic Kidney Diseases
 Autosomal dominant types
➢ Most common
➢ Cause symptoms later in life
➢ 2 types
• Chromosome 16
• Chromosome 4
➢ Reduction of intracellular calcium and excessive
concentrations of intracellular cAMP
➢ Normal functioning kidney tissue is slowly reduced
➢ Have many round cysts of varying sizes
➢ Other organs can develop cysts, especially the liver
Congenital Abnormalities (Cont.)
Cystic Kidney Diseases
 Autosomal dominant types
➢ Clinical manifestations
• Decreased ability to concentrate urine
• Hypertension
• Pain: most common
• Concomitant cystic liver involvement
➢ Diagnosis: genetic history and ultrasonography
➢ Treatment: primarily supportive, controlling blood
pressure and managing associated pathologies
• End-stage renal disease, dialysis initiated
http://thunder.biosci.umbc.edu/classes/biol414/spring2007/index.php/Cysts.