PATHOPHYSIOLOGICAL ASPECTS OF
RENAL FUNCTIONS. KIDNEY DISEASES
VLA, November 20, 2018
Filtration
Reabsorbtion
Secretion
KIDNEY - FUNCTION
NEPHRON: THE GLOMERULUS
Reabsorbtion in Henle´s loop
Insert fig. 17.15
DISTAL TUBULE
TUBULAR RESORPTION
 Proximal Tubules: GF: 120-125 mL/min
 Reabsorption of Na (55%), Cl, phosphate, amino acids,
glucose and bicarbonate (85%). Secretion of proton
(CA)
 Loop of Henle: (30 mL/min)
 Na/K/2Cl Cotransporter (25% Na reabsorbed)
 Water impermeable: Hypertonic medullary inst
 Ca & Mg paracellular diffusion
 Distal Tubules:
 Na/Cl cotransporter; Ca/Na counter transport
 Na Channels, K channels, H pump: Aldosterone reg.
 Collecting Tubules: 5-10 mL/min
 Water channels: Vasopressin regulated
 Ureters: 1-2 mL/min (stored in bladder until
voiding)
SUMMARY OF TUBULAR RESORPTIVE PROCESSES
SYSTEM RENIN-ANGIOTENSIN -ALDOSTERON
RPR, renin/prorenin receptor; Mas, mas oncogene, receptor for Ang 1–7; AT2R, angiotensin type 2 receptor
AT1R, angiotensin type 1 receptor, IRAP, insulin-regulated aminopeptidase; Ang IV receptor AMPA, aminopeptidase A;
AMPM, aminopeptidase M; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; NEP, neutral
endopeptidase.
PRORENIN INTERACTION WITH RENIN/PRORENIN
RECEPTOR (RPR, NGUYEN 2007 )
SYSTEM RENIN-ANGIOTENSIN
11β-HSD2 =
11β-hydroxy
steroid
dehydrogenase,
type 2
Vasopressin function . Stimulation of V2 receptor for ADH causes aquaporin2 insertion (using cAMP
second messenger) to apical membrane which enables water transport along the osmotic gradient.
REGULATION OF HYPOCALCEMIA BY KINDNEY
Calcitriol
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
Calcitriol
GLOMERULAR FILTRATION
 Rate (GFR): 120 mL/min (normal)
 Substances “Filtered”:
 water, electrolytes (Na, K, etc.), sugars
(glucose), nitrogenous waste (urea,
creatinine)
 Substances “Excluded”:
 Substances of size > 70 kDa
 Plasma protein bound substances
FACTORS DETERMINING GFR
RePa + RaPe
Ra + Re
PGC =
EFFECTIVE TRANSGLOMERULAR PRESSURE
Renal blood flow(RBF) and filtration
Kidneys autoregulation
1st Ohm´s law:
where P = Pa - Pe and R = Ra + Re
R must be variable , because renal perfusion as well as
GFR vary in large range of systemic blood pressure (90-190
mm Hg of mean arterial pressure.
RBF = P/R
P
RBF = ------------,
Ra + Re
KIDNEY SITES SUSCEPTIBLE TO RENAL DISEASE
 General: Renal medulla:
 Low oxygen environment: Ischemia
 Glomerulus:
 Structure predisposes it to immune complex
deposition and complement fixation
 Tubules:
 ischemia, inflammation
“Post-Renal” Structures (ureters, bladder)
 Malformations, Obstruction, Masses (i.e. cancer)
Diseases of the
glomerulus
Glomerulonephritis - Focal segmental
glomerulosclerosis - Membranoproliferative
glomerulonephritis - Membranous glomerulonephritis Nephritic
syndrome - Post-streptococcal
glomerulonephritis - Nephrotic syndrome (Minimal
change disease) - IgA nephropathy - Lupus nephritis Diabetic
nephropathy - Rapidly progressive
glomerulonephritis
Tubulointerstitial
diseases of the kidney
Interstitial nephritis - Pyelonephritis - Hydronephrosis Pyonephrosis
- Balkan nephropathy - Reflux
nephropathy
Renal failure Acute renal failure (Acute tubular necrosis) - Chronic
renal failure
Diseases of the renal
tubule and
other disorders of
kidney and ureter
Renal osteodystrophy - Nephrogenic diabetes insipidus
- Renal tubular acidosis - Nephroptosis - Ureterocele
Other diseases and
disorders of urinary
system
Cystitis (Interstitial cystitis, Trigonitis) - Neurogenic
bladder - Vesicointestinal fistula - Urethritis - Urethral
stricture - Urinary tract infection - Kidney stone
Tumors of the kidney Renal cell carcinoma - Wilms' tumor (children)
See also congenital conditions (Q60-Q64, 753)
RENAL DISEASE: GENERAL CHARACTERISTICS:
 Early Renal Disease: Abnormal urine volume
and/or composition (electrolytes, proteins, cells)
 Advanced: Edema, electrolyte abnormalities,
anemia, etc.
 Rate of Progression: Disease-dependent
 Disease Course: Transient-fatal: Disease-
dependent
 Pain: Variable, depending on nature of disease
 Renal Disease prominent in:
 Diabetes Mellitus
 Hypertension
 Autoimmune disorders (SLE)
CATEGORIZATION
 Generalized site of disease:
 Prerenal: Inadequate renal blood flow
 Intrarenal: Nephron damage
 Postrenal: Obstruction, structural defects
 Site of renal lesion (intrarenal)
 Glomerulopathy
 Nephritic:
 Nephrotic:
 Tubulointerstitial Disease
 Etiologic Factors: Infection, Diabetes, etc.
CHRONIC KIDNEY DISEASE
 is a progressive loss of renal function over a period
of months or years through five stages. Each stage
is a progression through an abnormally low and
progressively worse glomerular filtration rate, which
is usually determined indirectly by the creatinine
level in blood serum.
 Stage 1 CKD is mildly diminished renal function,
with few overt symptoms.
 Stage 5 CKD is a severe illness and requires some
form of renal replacement therapy (dialysis or
renal transplant). Stage 5 CKD is also called endstage
renal disease (ESRD).
PROTEINURIA
 In the normal person, urinary protein excretion is
less than 150 mg per day (with most subjects
being under 100 mg per day) and consists mostly
of filtered plasma proteins (60%) and tubular
proteins (40%).
 The main plasma protein in the urine is albumin,
constituting about 20% of the total normal daily
protein excretion.
 In normal subjects the daily amount of albumin is
less than 20 mg.
PROTEINURIA
 Proteinuria usually reflects an increase in
glomerular permeability for normally nonfiltered
(?) plasma macromolecules such
as albumin.
 A 24-hour urine collection containing more
than 150 mg of protein is abnormal.
 Significant proteinuria is suspected when a
dipstick test of the urine is persistently
positive for protein. In such a situation the
daily protein excretion will usually exceed
300-500 mg per day.
MICROALBUMINURIA
 is defined by the presence of >30 and <300 mg of
albuminuria daily.
 The albumin to creatinine concentration of >30 mg per
gram of creatinine correlates very well with a 24-hour urine
albumin measurement. Its detection in Type I diabetes
mellitus is the earliest clinical evidence of diabetic
nephropathy. Transient increases in urinary albumin
excretion may be seen in short-term hyperglycemia,
exercise, urinary tract infections, marked hypertension,
heart failure, and acute febrile illnesses. There is also
diurnal variation in urinary albumin excretion.
 Confirmation of microalbuminuria requires verification on 2
or 3 collections over 3 to 6 months.
Definition of Abnormalities in Albumin Excretion
Category Time Collection
Spot
Collection
24-h
Collection
(mg/24 h)
(&microg/
min)
(&microg/g
creatinine)
Normal < 30 < 20 < 30
Microalbuminuria 30-299 20-199 30-299
Clinical proteinuria > 300 > 200 > 300
GLOMERULAR PROTEINURIA

The glomerular filtration barrier is composed of
the endothelial cell, the basement membrane,
and the epithelial cell foot processes.
 Proteinuria occurring in glomerular disease is due
to increased filtration of albumin and other
macromolecules across the glomerular
basement membrane. This occurs because of an
alteration in both the charge selectivity and size
selectivity of the glomerular barrier.
GLOMERULAR PROTEINURIA
 Normally the basement membrane and
endothelial cells possess a negative charge.
Plasma albumin, which also possesses a negative
charge, is repelled by the normal negative
charge on the basement membrane and the
intact endothelial cells. Circulating IgG has a
neutral or positive charge and is not restricted by
a negative charge on the basement membrane.
Rather, immunoglobulins are restricted by the size
selective barrier of the membrane and the
epithelial slit diaphragm located across the
spaces between the epithelial foot processes.
GLOMERULAR PROTEINURIA
 In glomerular disease, the injury to the glomerular
basement membrane causes proteinuria due to a
loss in negative charge as well as from an increase
in the number of larger non-selective pores.
 Glomerular diseases are also accompanied by
disruption and loss of the epithelial foot process
covering of the basement membrane.
 It appears that the increased protein leakage
occurs especially at the sites of this epithelial
alteration.
TUBULAR PROTEINURIA

OVERFLOW PROTEINURIA

Increased excretion of low molecular
weight proteins might be seen in states
where there is significant increased
production of these proteins, as in multiple
myeloma.
 The proteinuria results from the fact that the
amount of these proteins filtered exceeds
the reabsorptive capacity of the proximal
tubule.
Clin Orthop Relat Res. 2011 Jun; 469(6): 1651–1659.
CLINICAL SIGNS
 Most patients with proteinuria have no signs
or symptoms from the proteinuria.
 In states of heavy (nephrotic range)
proteinuria exceeding 3 g daily, the patient
might report foamy urine and might
demonstrate edema.
 The foamy urine is due to increased lipids in
the urine, which alters the surface tension
of the urine. Lipiduria is caused by the
filtration of lipoproteins across the
damaged glomerular barrier. On urine
microscopy lipiduria might appear as free
fat, or as fat droplets in tubular cells or casts
where they are referred to as oval fat
bodies or fatty casts respectively.
CLINICAL SIGNS
 Edema, which frequently accompanies
nephrotic range proteinuria, is caused by
reduction of plasma oncotic pressure due
to reduced plasma albumin.
Hypoalbuminemia is the result of increased
glomerular losses and/or defective
synthesis of albumin. The loss of albumin
stimulates the liver synthetic activity, which
also contributes to increased lipoprotein
production and hyperlipidemia.
Differential Diagnosis of Kidney Disease by
Varying Levels of Proteinuria
Proteinuria Less than 1-2 Grams Daily
•Nephrosclerosis*
•Tubulointerstitial disease*
•Polycystic kidney disease
•Orthostatic proteinuria
•More benign forms of glomerular disease (eg, IgA nephritis)*
Proteinuria Greater than 3.5 Grams Daily (Nephrotic-Range)
Primary glomerular disease
•Minimal change disease
•Membranous glomerulonephritis*
•Focal and segmental glomerulosclerosis*
•Membranoproliferative glomerulonephritis
Secondary nephrotic syndrome: glomerular disease
associated
with specific causes
•Systemic disease
•Diabetic nephropathy*
•Systemic Lupus Erythematosus
•Amyloidosis
•Vasculitic-immunologic diseases (Wegener's,
Goodpasture's, Polyarteritis)
•Infectious disease
•Post-streptococcal glomerulonephritis
•Hepatitis B and C*
•Bacterial endocarditis
•HIV*
•Malignancies
•Lymphoproliferative disorders, Hodgkin's (minimal
change)
•Solid tumors (membranous)
•Medications:
•Nonsteroidal anti-inflammatory drugs*
•Gold, mercury, heavy metals
•Penicillamine
•Lithium
•"Street" heroin
•Hereditary and metabolic disorders
•Alport's syndrome
•Fabry's disease
•Sickle cell anemia
•Nail-patella syndrome
•Others
•Accelerated hypertensive nephrosclerosis
•Massive obesity
•Transplant rejection nephropathy
* Most common disorders in adults
GLOMERULONEPHRITIS:
CLINICAL MANIFESTATIONS
 Proteinuria and hematuria: damage to
capillary wall allows “leakage”
 Decreased GFR:
 Infiltration of glomerular capillaries with
inflammatory cells, OR
 Expansion of contractile mesangial cells
 Edema and hypertension: Fluid and salt
overload from decreased GFR
 Transient decrease in serum complement
 Transient elevations antibody to
streptococcal antigen
ACUTE GLOMERULONEPHRITIS:
 Clinical Presentation
 Abrupt hematuria and proteinuria
 reduced GFR, salt and water retention
 Pathology & Pathogenesis
 Infection: Immune response to pathogen (i.e.
Streptococci) antigen resulting in deposition of
immune complexes and complement in
glomerular capillary bed (intrarenal!)
 Onset:7-10 days after initial infection
 Full recovery typically occurs within weeks on
infection
Clin J Am Soc Nephrol (2017) 11:1856–1866.
Conditions within the kidney that are conducive to complement (C )
activation.
 The C cascade is activated by distinct mechanisms at various
ultrastructural locations within the kidney.
 Immune-complexes can deposit in the mesangium and at different
locations within the glomerular capillary wall.
 In some diseases, autoantibodies bind to specific renal antigens.
 Other conditions in the kidney that favor C activation are increased
concentrations of C proteins in the efferent vessels, low pH, increased
local concentrations of C proteins due to production by tubular epithelial
cells, and high concentrations of ammonia which can activate the
alternative pathway.
 The glomerular basement membrane does not express C regulatory
proteins, although factor H controls alternative pathway activation on the
glomerular basement membrane. The apical surface of tubular epithelial
cells also does not express C regulatory proteins, and alternative pathway
proteins may be activated at this location in proteinuric conditions.
EC, endothelial cell; PO, podocyte; fB, factor B; fD, factor D.
Clin J Am Soc Nephrol (2017) 11:1856–1866.
GLOMERULAR CAPILLARY:
NORMAL VERSUS PATHOLOGY
GLOMERULAR CAPILLARY PATHOLOGY
1. Membranous nephropathy:
Subepithelial deposits
2. Post-infectious glomerulonephritis:
Subepithelial
3. Lupus glomerulonephritis:
Subendothelial deposits
4. IgA Nephropathy: Mesangial deposits
5. Goodpasture’s Syndrome: Antibody
binding to GBM
6. Glomerular injury with proteinuria:
Podocyte effacement
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
 Clinical Presentation: “Intermediate” stage
 Failure to recover from Acute
Glomerulonephritis: Origin unknown
 Worsening renal function with irreversible and
complete renal failure as the outcome
 Pathology & Pathogenesis
 Intermediate stage between “Acute” and
“Chronic”
 Extracapillary cellular proliferation: 70% of
glomeruli
 Basement membrane gap/discontinuities
 Deposition of anti-GBM antibodies or granular
immunoglobulins
CHRONIC GLOMERULONEPHRITIS
 Clinical Presentation
 Slow progression from acute disease to
chronic renal failure (5-20 years)
 Pathology & Pathogenesis
 Capillary or mesangial cellular proliferation
 Structural obliteration of glomeruli: sclerosing
 Subepithelial proteinaceous deposits:
Membranous glomerulonephritis
NEPHROTIC SYNDROME
 Clinical Presentation
 Marked proteinuria (albuminuria) >3.5 g/24hr
with hypoalbuminemia
 Edema
 Hyperlipidemia
 Fat bodies in the urine
 Pathology & Pathogenesis
 Minimal cellular infiltration of glomeruli
 Deposition of antigen-antibody complexes in
the subepithelium space
NEPHROTIC SYNDROME: CLINICAL MANIFESTATIONS
 Decreased oncotic pressure: loss of serum protein:
 Intravascular volume depletion with syncope, shock and
acute renal failure
 Activation of renin-angiotensin-aldosterone system
 Activation of sympathetic nervous system
 Increased secretion of vasopressin
 Hyperlipidemia: Increases hepatic VLDL production
 Loss of other plasma proteins:
 Increased susceptibility to infection
 Hypercoagulability
 Vitamin D deficiency: loss of Vit D binding protein
 Altered thyroxine binding protein/thyroid tests
NEFROTIC VS. NEFRITIC SYNDROME
 Nephrotic diseases:
 Severe proteinuria
 Immune complex deposits in subepithelium
space
 No cell inflammation reaction
 Increased TAG (as a response to severe chronic
proteinuria)
 Nephritic diseases
 Variable proteinuria
 Immune complex deposits in subendothelial
space and/ or in basal membrane
 Cell inflammatory reaction
THANK YOU FOR YOUR ATTENTION