Nephrology Lecture 3 PDF

FACULTY of MEDICINE in ENGLISH LECTURE 3 TUBULO-INTERSTITIAL NEPHRITIS URINARY TRACT INFECTIONS Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 04th of December 2024...

FACULTY of MEDICINE in ENGLISH LECTURE 3 TUBULO-INTERSTITIAL NEPHRITIS URINARY TRACT INFECTIONS Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 04th of December 2024 Pentru uz intern Este interzisă copierea și distribuirea neautorizată a acestui material. At the end of this lecture, participants will be able to: - recognize acute and chronic tubulo-interstitial nephritis; - identify obstructive and reflux nephropathy; - identify the types of lower and upper urinary tract infections;  TUBULOINTERSTITIAL NEPHRITIS (TIN) - The renal interstitium accounts for 80% of the kidney's volume, occupying the space between glomeruli, tubules, and blood vessels. It is more abundant in the medulla than in the cortex and merges with the basement membranes of the tubules and blood vessels.  TUBULOINTERSTITIAL NEPHRITIS (TIN) - The interstitium is composed of a fibrillar matrix containing proteoglycans and glycoproteins, which facilitates the transfer of water and solutes between the various nephron structures and blood vessels. The matrix contains relatively few resident (fibroblasts) or migrated cells (monocytes, macrophages, lymphocytes). - Fibroblasts synthesize the matrix and produce erythropoietin. Under pathological conditions, they contribute to fibrosis, and a reduction in their number explains the severity of anemia in certain chronic tubulointerstitial nephropathies.  Plate 1-18 An TUBULO-INTERSTITIAL O NEPHRITIS N (TIN) VERVIEW OF THE EPHRON Fibrous capsule Long-looped nephron Short-looped ne Each kidney possesses an average of 600,000 to 1,400,000 tubular structures called nephrons, which contain a lar zone Subcapsu series of histologically distinct segments that alter the concentration and contents of urine. The major seg- ments of each nephron are known as the glomerulus, proximal tubule, thin limb, distal tubule, and collecting Distal Renal cortex duct. The proximal and distal tubules are both divided convoluted into convoluted and straight parts, while the thin limb is tubule divided into descending and ascending parts. Juxtamedullary glomerulus The arrangement of these different nephron seg- ments gives rise to the two grossly visible zones in the - The tubules have a strange anatomical and kidney, known as the cortex and medulla. The medulla is divided into an outer zone (which is further subdi- Proximal convoluted tubule vided into outer and inner stripes) and an inner zone. functional relationship with the interstitium and The boundaries of these various regions are marked by the transition sites between different nephron seg- ments, as described later. Proximal straight react synergistically with it under pathological Outer stripe tubule Outer zone GLOMERULUS AND PROXIMAL conditions, so the term tubulo-interstitial CONVOLUTED TUBULE Thick The initial formation of urine occurs at the interface ascending stripe Inner between the glomerular capillaries, which are arranged limb Henle’s nephritis is more accurate than interstitial in a spherical tuft, and the first part of the nephron, an epithelial-lined sac known as Bowman’s capsule. The glomerular capillaries and Bowman’s capsule are loop Collecting nephritis. Extensive damage to the tubules and together knows as the glomerulus (or renal corpuscle). Renal medulla (pyramid) As blood from an afferent arteriole passes through the glomerular capillaries, plasma and non–protein bound Descending interstitium in acute tubulo-interstitial nephritis solutes are filtered into the area bounded by Bowman’s thin limb capsule, known as Bowman’s space, to form primitive urine. All nonfiltered blood is carried away from the Ascending often manifests clinically as acute kidney injury. glomerular capillaries in an efferent arteriole. thin limb Bowman’s space conveys the primitive urine to the first part of the proximal tubule, known as the proximal Inner zone convoluted tubule, which takes a very tortuous course through a small region of the cortex. The proximal con- voluted tubule then transitions to the proximal straight The Netter Collection of Medical tubule, which is the first part of the loop of Henle. Ilustrations: Urinary System, LOOP OF HENLE Volume 5, Elsevier, Second After the proximal convoluted tubule, each nephron Edition, 2012. plunges into the medulla, makes a hairpin turn, and Opening then returns to the cortex near its parent glomerulus. of papillary This region of each nephron is known as the loop of duct Henle, and it contains the proximal straight tubule, thin limb, and distal straight tubule (more commonly known as the thick ascending limb). The proximal straight tubule, described above, origi- Cribriform area of renal papilla nates in the cortex and courses to the border between the outer and inner stripes of the outer zone of the medulla. It then transitions to the first part of the thin this point it transitions to the thick ascending limb, where it transitio limb, known as the descending thin limb. which courses back toward the cortex. Near this transitio The remaining structure of the loop of Henle differs Thus, based on the above descriptions, two different known as the mac based on the location of the nephron’s parent glomeru- populations of nephrons can be distinguished: short- with the nephron’s lus. In nephrons associated with glomeruli in more looped nephrons, which are associated with superficial The distal conv superficial regions of the renal cortex, the descending and midcortical glomeruli, and long-looped nephrons, voluted tubule, ta thin limb continues until reaching the border between which are associated with juxtamedullary glomeruli. small area of the the inner zone of the medulla and the inner stripe of Long-looped nephrons have higher urine-concentrating necting segment (o the outer zone of the medulla. At this point, it transi- capabilities than short-looped nephrons (see Plate collecting duct.  TUBULO-INTERSTITIAL NEPHRITIS (TIN) Distal tubular acidosis: Plate 1-18 OVERVIEW OF THE NEPHRON Long-looped nephron acidosis, hyperkalemia; Anatomy of the Urinary Tract Short-looped nephron - Selective damage to the Each kidney possesses an average of 600,000 to 1,400,000 Fibrous capsule Superficial glomerulus lar zone tubules explains some of the tubular structures called nephrons, which contain a Subcapsu series of histologically distinct segments that alter the concentration and contents of urine. The major seg- Proximal convoluted tubule ments of each nephron are known as the glomerulus, clinical manifestations of proximal tubule, thin limb, distal tubule, and collecting Distal Distal convoluted tubule Renal cortex duct. The proximal and distal tubules are both divided convoluted into convoluted and straight parts, while the thin limb is tubule Proximal straight tubule tubulointerstitial nephritis: divided into descending and ascending parts. Juxtamedullary glomerulus The arrangement of these different nephron seg- ments gives rise to the two grossly visible zones in the Henle’s loop kidney, known as the cortex and medulla. The medulla Proximal convoluted is divided into an outer zone (which is further subdi- tubule vided into outer and inner stripes) and an inner zone. Thick ascending limb The boundaries of these various regions are marked by (distal straight tubule) the transition sites between different nephron seg- Proximal ments, as described later. straight Outer stripe tubule Outer zone GLOMERULUS AND PROXIMAL CONVOLUTED TUBULE Thick Descending thin limb The initial formation of urine occurs at the interface ascending stripe Inner between the glomerular capillaries, which are arranged limb Henle’s in a spherical tuft, and the first part of the nephron, loop an epithelial-lined sac known as Bowman’s capsule. The glomerular capillaries and Bowman’s capsule are Collecting duct together knows as the glomerulus (or renal corpuscle). Fanconi syndrome: glycosuria, Renal medulla (pyramid) As blood from an afferent arteriole passes through the glomerular capillaries, plasma and non–protein bound Descending solutes are filtered into the area bounded by Bowman’s thin limb aminoaciduria, phosphaturia, capsule, known as Bowman’s space, to form primitive Glomerular capillaries urine. All nonfiltered blood is carried away from the and Bowman’s capsule Ascending glomerular capillaries in an efferent arteriole. thin limb Bowman’s space conveys the primitive urine to the Afferent and efferent proximal tubular acidosis; first part of the proximal tubule, known as the proximal Nephrogenic diabetes insipidus: glomerular arterioles Inner zone convoluted tubule, which takes a very tortuous course through a small region of the cortex. The proximal con- Proximal convoluted tubule voluted tubule then transitions to the proximal straight urine concentration defect. Proximal straight tubule tubule, which is the first part of the loop of Henle. Henle’s loop The Netter Collection of Medical Thin limb LOOP OF HENLE Ilustrations: Urinary System, After the proximal convoluted tubule, each nephron Thick ascending limb plunges into the medulla, makes a hairpin turn, and Volume 5, Elsevier, Opening Second (distal straight tubule) then returns to the cortex near its parent glomerulus. of papillary This region of each nephron is known as the loop of Edition, 2012. Distal convoluted tubule duct Macula densa Henle, and it contains the proximal straight tubule, thin limb, and distal straight tubule (more commonly known as the thick ascending limb). The proximal straight tubule, described above, origi- Collecting ducts Cribriform area of renal papilla nates in the cortex and courses to the border between the outer and inner stripes of the outer zone of the medulla. It then transitions to the first part of the thin this point it transitions to the thick ascending limb, where it transitions to the distal convoluted tubule. limb, known as the descending thin limb. which courses back toward the cortex. Near this transition point is a specialized group of cells The remaining structure of the loop of Henle differs Thus, based on the above descriptions, two different known as the macula densa, which make direct contact based on the location of the nephron’s parent glomeru- populations of nephrons can be distinguished: short- with the nephron’s parent glomerulus. lus. In nephrons associated with glomeruli in more looped nephrons, which are associated with superficial The distal convoluted tubule, like the proximal con- superficial regions of the renal cortex, the descending and midcortical glomeruli, and long-looped nephrons, voluted tubule, takes a very tortuous course within a thin limb continues until reaching the border between which are associated with juxtamedullary glomeruli. small area of the cortex. It transitions to a short con- the inner zone of the medulla and the inner stripe of Long-looped nephrons have higher urine-concentrating necting segment (or tubule), which in turn leads to the the outer zone of the medulla. At this point, it transi- capabilities than short-looped nephrons (see Plate collecting duct. tions to the thick ascending limb, which makes a hairpin 3-15); however, short-looped nephrons are far more The collecting duct courses from the cortex toward turn and courses back toward the cortex. numerous, accounting for 85% of the total nephron the medulla adjacent to ducts from neighboring neph-  CLASSIFICATION Acute Tubulo-interstitial nephritis - Sepsis; Acute tubular necrosis - Ischemia; - Direct toxicity - Medications; Acute hypersensitivity - Systemic diseases; interstitial nephritis - Distal response to infections Acute infectious tubulo- - Ascending - pyelonephritis; interstitial nephritis - Descending – hematogenous.  Plate 4-8 CAUSES AND PRESENTATION OF MINIMAL CHAN Major causes ETIOLOGY MINIMAL CHANGE DISEASE Acute Tubulo-interstitial nephritis Idiopathic Majority Minimal change disease (MCD, also known as nil of cases disease and lipoid nephrosis) is the leading cause of nephrotic syndrome in children, accounting for 90% of Medications The Netter Collection of Medical Ilustrations: Allerg cases in this population, and a major cause of nephrotic NSAIDs Gold Po syndrome in adults. In addition to its predilection for Urinary LithiumSystem, Volume 5, Elsevier, Second Alpha-interferon Be children, MCD also occurs more frequently in Asians Ampicillin Edition, 2012. Probenecid D Rifampin and Caucasians than in African-Americans. The name of this disease refers to the seemingly normal appearance of glomeruli when visualized using - Medications (75%); Acute hypersensitivity light microscopy. On electron microscopy, however, diffuse foot process effacement can be seen, which is - Systemic diseases; interstitial nephritis the basis for the proteinuria. The vast majority (>85%) of MCD cases are primary, idiopathic phenomena. In the remaining cases, MCD occurs secondary to a systemic insult, such as drugs - Distal response to infections (e.g., NSAIDs, lithium), neoplasms (especially hemato- logic malignancies), infections (e.g., tuberculosis, syphi- lis), and allergies to common irritants (i.e., poison ivy, Infections Malig ragweed, poison oak, bee stings, certain foods). Tuberculosis H Syphilis N Le PATHOPHYSIOLOGY - antibiotics (penicillins, quinolones, The precise mechanism of MCD is not known. One sulfonamides); Clinical features theory speculates that dysfunctional T-cells produce a - proton pump inhibitors; cytokine called the glomerular permeability factor, which injures podocytes (visceral epithelial cells) and leads to foot process effacement. Loss of the slit dia- - nonsteroidal anti-inflammatory drugs (NSAIDs) phragm architecture, which constitutes the normal barrier to protein filtration, leads to proteinuria. B cells may also play a role, either by producing the glomerular permeability factor or, alternatively, by secreting an antibody that targets a glomerular antigen. The immune-mediated hypothesis is supported by the efficacy of immunomodulatory treatments, as well as the fact that MCD may occur secondary to allergens, Edema infections, and cancers of the immune system. In cases of idiopathic MCD, it is not clear what would trigger this abnormal immune response. Some have postulated that viral or bacterial infections may be responsible, although at present there is no evidence for this claim. Despite the damage to podocytes, the remainder of  ETIOLOGY Acute Tubulo-interstitial nephritis - Medications (75%); Acute hypersensitivity - Systemic imune diseases (10-15%); interstitial nephritis - Distal response to infections (10%). - Sjogren syndrome; - Sarcoidosis; - Systemic lupus erythematosus; - Acute interstitial nephritis with uveitis.  ETIOLOGY Acute Tubulo-interstitial nephritis - Medications (75%); Acute hypersensitivity interstitial nephritis - Systemic imune diseases (10-15%); - Distal response to infections (10%). - Leptospira; - Legionella; - Streptococcus sp; - Corynebacterium sp; - Rickettsia; - Ebstein Barr virus.  GLOMERULONEPHRITIS AND THE ACUTE NEPHRITIC SYNDROME 1 No known antigen or antibody involvement PATHOGENESIS 2 Circulating antibody against ‘planted’ antigen Field, Michael. The Renal System, Elsevier publishing house, 2th edition, 2010. - The lesions have an immunological basis. Etiological agents release tubular Deposition of circulating antigens, modified by drugs or infection, which are then 3 implanted in the immune complex interstitium, where they act as incomplete antigens (haptens), binding to the tubular basement membrane. Subepithelial Subendothelial Antibody against intrinsic glomerular antigen 4 - The mechanism of interstitial injury appears to be immunological, but it is not well understood. Although specific antibodies (humoral immunity) are GBM present, immunofluorescence is positive in only a few cases, suggesting that cellular immunity may also be involved. Leukocytes and platelets Complement Fig. 7.6 C Coagulation factors Cytokines circumfere Eicosanoids Fig. 7.5 Schematic representation of immunopathogenetic epithelia mechanisms of acute glomerulonephritis and the influence of other infiltrate cellular and humoral mediators. Antigens may be deposited on the may exp  CHAPTER 1 Renal Anatomy 9 HISTOLOGY A B Fig. 1.11 Tubules of the Renal Cortex. (A) Proximal convoluted tubule is equipped with a brush border and a prominent vacuolar apparatus in the apical cytoplasm. The rest of the cytoplasm is occupied by a basal R.J.Johnson, labyrinth consisting J.Floege,M.Tonelli. of large mitochondria Comprehensive associated with basolateral clinical cell membranes. (B) Distal convoluted nephrology, tubule also has Elsevier interdigitated basolateral publishing cell house, membranes intimately 7 th edition, associated 2023. with large mitochondria. In contrast to the proximal tubule, however, the apical surface is amplied only by some stubby microvilli. (TEM; A, ×1530; B, ×1830.) reabsorption specic for the proximal tubule is the Na+-H+ exchanger of the thin limbs for the generation of the osmotic medullary gradient (NHE3) that is located in the plasma membrane of the apical micro- is debated. villi and accounts for reabsorption of most of the ltered sodium. - Abundant interstitial infiltrate: mononuclear cells (monocytes, Other sodium coupled transporters in the microvillous membrane are the sodium-glucose cotransporters SGLT2 and SGLT1 and several sodium-phosphate cotransporters. The abundance of channel protein Distal Straight Tubule (Thick Ascending Limb of Henle’s Loop) The thick ascending limb of Henle’s loop is often called the diluting segment. It is water impermeable but reabsorbs considerable amounts lymphocytes, plasma cells), neutrophils, and eosinophils; aquaporin 1 in the apical microvillous membrane and the basolateral of sodium and chloride, resulting in the separation of salt from water. cell membrane accounts for the high hydraulic permeability for water The salt is trapped in the medulla (see Fig. 1.12), whereas the water of this epithelium. An apical tubulovesicular compartment is part of is carried away into the cortex, where it may return into the systemic the prominent endosomal-lysosomal system and is responsible for the circulation. The specic transporter for Na+ reabsorption in this seg- - Marked interstitial edema; reabsorption of macromolecules (active peptides, polypeptides, and ment is the Na+-K+-2Cl cotransporter 2 (NKCC2),39 which is speci- proteins such as albumin) that have passed the glomerular lter. cally inhibited by loop diuretics such as furosemide. This transporter is The S3 and portions of the S2 segments are engaged in many secre- inserted in the luminal membrane, which is amplied by only solitary tory processes of toxic substances and drugs via organic anion trans- microvilli. The tight junctions of the thick ascending limb are elon- - Tubular lesions (necrosis, tubulitis). porters and an organic cation transporter (OCT). Proximal tubule cells gated by lateral interdigitation of the cells. They have a comparatively are electrically coupled by gap junctions (Nexus). low overall permeability; however, they contain the protein Claudin 16 for paracellular reabsorption of divalent ions, notably of magne- Intermediate Tubule sium. The cells are heavily interdigitated by basolateral cell processes, The intermediate tubule includes the thin portion of Henle’s loop, thin which are associated with large mitochondria supplying the energy for descending and (only in long loops) thin ascending limbs (Fig. 1.12; the transepithelial transport. The cells synthesize the Tamm-Horsfall see also Fig. 1.2). Thin descending limbs of short loops and those of protein and release it into the tubular lumen. This protein may help long loops are equipped with different epithelia. The thin descend- prevent the formation of kidney stones. A short distance before the ing limbs of short loops have an extremely at epithelium that, in its transition to the distal convoluted tubule, the thick ascending limb beginning part, is permeable to water, and, in its distal part, contains contains the macula densa, which adheres to the glomerulus of the the urea transporter UT-A2 responsible for the uptake of urea com- same nephron (see Juxtaglomerular Apparatus). ing up from the inner medulla (urea recycling).38 The thin descending limbs of long loops, in their initial parts within the inner stripe, are Distal Convoluted Tubule quite permeable to Na+ and Cl (uptake from the interstitial space) and The epithelium exhibits the most extensive basolateral interdigita- have a considerable Na+,K+-ATPase activity, the relevance of which is tion of the cells and the greatest numerical density of mitochondria unknown. Along their course down through the inner medulla they compared with all other nephron portions (see Fig. 1.11). Apically, lose their salt permeability becoming permeable to water. The tran- the cells are equipped with numerous solitary microvilli. The specic sition to the ascending thin limb epithelium occurs already before Na+ transporter of the distal convoluted tubule is the luminal Na+-Cl the bend. The ascending thin limbs have a heavily interdigitated epi- cotransport system (NCC), which can be inhibited by the thiazide thelium highly permeable for ions releasing them into the interstitial diuretics. Magnesium is reabsorbed via the transient receptor potential space but impermeable for water. The relevance of transport functions channel melastatin subtype 6 (TRPM6) in the luminal membrane40  Plate 4-8 CAUSES AND PRESENTATION OF MINIMAL CHAN Major causes CLINICAL FEATURES MINIMAL CHANGE DISEASE Idiopathic Majority Minimal change disease (MCD, also known as nil of cases disease and lipoid nephrosis) is the leading cause of nephrotic syndrome in children, accounting for 90% of Medications The Netter Collection of Medical Ilustrations: Allerg cases in this population, and a major cause of nephrotic NSAIDs Gold Po syndrome in adults. In addition to its predilection for Urinary LithiumSystem, Volume 5, Elsevier, Second Alpha-interferon Be children, MCD also occurs more frequently in Asians Ampicillin Edition, 2012. Probenecid D Rifampin and Caucasians than in African-Americans. The name of this disease refers to the seemingly normal appearance of glomeruli when visualized using light microscopy. On electron microscopy, however, diffuse foot process effacement can be seen, which is the basis for the proteinuria. - The onset is usually a few days or weeks after starting treatment with The vast majority (>85%) of MCD cases are primary, idiopathic phenomena. In the remaining cases, MCD the responsible drug or following the causal infection, but it can also occurs secondary to a systemic insult, such as drugs (e.g., NSAIDs, lithium), neoplasms (especially hemato- logic malignancies), infections (e.g., tuberculosis, syphi- occur after several months in the case of nonsteroidal ragweed, poison oak, bee stings, certain foods). anti-inflammatory lis), and allergies to common irritants (i.e., poison ivy, Infections Tuberculosis Malig H drugs and proton pump inhibitors. Syphilis N Le PATHOPHYSIOLOGY Clinical features The precise mechanism of MCD is not known. One theory speculates that dysfunctional T-cells produce a cytokine called the glomerular permeability factor, which injures podocytes (visceral epithelial cells) and leads to foot process effacement. Loss of the slit dia- phragm architecture, which constitutes the normal barrier to protein filtration, leads to proteinuria. B cells may also play a role, either by producing the glomerular permeability factor or, alternatively, by secreting an antibody that targets a glomerular antigen. The immune-mediated hypothesis is supported by the efficacy of immunomodulatory treatments, as well as the fact that MCD may occur secondary to allergens, Edema infections, and cancers of the immune system. In cases of idiopathic MCD, it is not clear what would trigger this abnormal immune response. Some have postulated that viral or bacterial infections may be responsible, although at present there is no evidence for this claim. Despite the damage to podocytes, the remainder of  RENAL MANIFESTATIONS 710 CHAPTER 107 STRUCTURE AND FUNCTION OF Cortex The glomer - Oliguria - acute kidney injury is the most common Corticomedullary junction Medulla entering the ap countertransp presentation - in one-third of cases, it is severe Papilla tubule contain and Na+-coup C alyx transported by enough to require hemodialysis; resulting in lo tight junction - Urine examination: reduced quantitative In the thic cotransporter enter the cell, proteinuria, leukocyturia (eosinophiluria), leukocyte C apsule ing in depolar Renal artery convoluted tub casts (sometimes with eosinophils), and occasionally Renal vein conducts Na+ Na+, K+-ATPa segment, the m Renal pelvis microscopic hematuria, but no dysmorphic RBC or Arcuate through secre In the princ casts; artery glomerulosa o Aldosterone in remaining in t - Sometimes, acute interstitial nephritis caused by Ureter (ENaC) and b A number o NSAIDs may lead to nephrotic-range proteinuria; by atrial natriu Renal pyramid to volume ov FIGURE 107-1. Sagittal section of the human kidney depicting gross anatomy and the afferent a - Ultrasound: enlarged kidneys, edema of the renal Goldman-Cecil Medicine, Elsevier publishing house, 26th organization. lowering the o edition, 2020. by inhibiting t reabsorption o pyramids. or apical surface (facing the urine) and basolateral surface (facing the blood) THE K differentially express various proteins and lipids. For example, the apical mem- OSMO brane often has microvilli or cilia, whereas the basolateral membrane does Water moves not. Polarized endocytosis and exocytosis are often important in the regulation conducting ch of the number of transport proteins on the apical surface. In addition, epithelia water) is stric are connected to one another by tight junctions, which confer a characteristic mechanisms t ionic permeability on the epithelial sheet. Transepithelial transport occurs the kidney can largely through the cell, but transport also can occur through the tight junc- limb, distal tub tion (the paracellular pathway). For instance, sodium transport begins with the urine. The entry at the luminal surface down an electrochemical gradient, whereas its medulla, whe exit at the basolateral surface is uphill and requires adenosine triphosphate concentrate th  EXTRARENAL MANIFESTATIONS - Low-grade fever/fever, skin rashes, arthralgia, and eosinophilia occur in less than half of cases, but their association with acute kidney injury is suggestive of acute interstitial nephritis. Kumar and Clark¢s. Clinical Medicine, Elsevier publishing house, 10th edition, July 2020. - In acute interstitial nephritis associated with systemic diseases—Sjogren's syndrome, sarcoidosis, systemic lupus erythematosus—acute kidney injury is accompanied by the manifestations of the underlying disease. Similarly, tubulointerstitial nephritis associated with uveitis can be suspected in young women, based on the association of acute kidney injury with uveitis. partial thromboplastin time, and platelet count. Any bleeding diathesis should be corrected, if possible, before the procedure. Most patients can undergo a percutaneous biopsy, which is performed at the bedside; however, select patients may require alternate approaches, including open, laparoscopic, and transjugular biopsies. The 4. The site is sterilized and anesthetized. 5. The biopsy needle is cocked. The first twist retracts major indications for these techniques include an For larger gauge needles, a scalpel may the cannula. The second twist retracts the stylet. uncorrectable bleeding diathesis, morbid obesity, soli- be used to make a small incision at the tary kidney, infection of the skin over the kidneys, and site of planned needle entry. failed percutaneous attempts. For a percutaneous biopsy, most patients should be placed prone, with a folded pillow under the abdomen. The Netter An ultrasound is performed to visualize the kidney and Collection of determine the location and angle of needle insertion. Medical The upper or lower pole should be targeted so that only cortical tissue is acquired. Hydronephrosis, multiple cysts, or small hyperechoic kidneys may be seen, which increase the bleeding risk and should be considered DIAGNOSIS Ilustrations: Urinary relative contraindications. System, Once the initial ultrasound is complete, the site is Volume 5, dressed and draped in normal sterile fashion. The site Elsevier, is injected with a local anesthetic, and a scalpel may be used to nick the skin at the area of planned needle inser- Second tion. The biopsy needle, which consists of a spring- Edition, 2012. loaded outer cannula and inner stylet, is then cocked as shown in the diagram. The needle is passed through the skin into the renal parenchyma, often using ultrasound 6. The biopsy needle is inserted. When the tip is in 7. Once proper positioning is confirmed, the for real-time guidance. The patient is instructed to hold the renal parenchyma, the needle will be deflected actuator is depressed, causing the stylet and Acute kidney injury (without an obvious cause) his or her breath, and then the actuator button is depressed, causing rapid advancement of both the inner stylet and outer cannula to the device’s predetermined by the movement of the kidney during respiration. Proper positioning may also be confirmed using ultrasound guidance. cannula to rapidly advance into the paren- chyma. The needle is then withdrawn. + penetration depth. A tissue core is acquired as the cannula rapidly passes over the stylet. Two or three cores should be acquired to ensure an adequate sample. hematoxylin and eosin, periodic acid–Schiff, Jones’ system, perinephric space, or subcapsular space. Patients The adequacy of the tissue cores can be assessed silver methenamine, and trichrome. should thus be monitored for approximately 4 to 6 leukocyturia (eosinophilia/eosinophiluria) using low-power microscopic examination. An adequate sample should contain a minimum of 8 to 10 glomeruli. The cores should be transported in normal saline to the COMPLICATIONS hours after the procedure, with vital signs, hemoglobin levels, and urine color noted. Some centers perform a follow-up computed tomography (CT) scan or ultra- + pathology laboratory or placed in fixatives if the labora- The main complications of a renal biopsy include sound a few hours after the biopsy. In the event of a tory is not on site. A renal pathologist then examines bleeding, pain, damage/puncture of surrounding struc- major bleed, transfusions or therapeutic procedures the tissue using light microscopy, electron microscopy, tures (liver, spleen, bowel), and arteriovenous fistula (e.g., angioembolization or laparotomy) should be per- and immunofluorescence or immunohistochemistry. formation. Bleeding is by far the most common com- formed as needed. In very rare cases, a renal biopsy medical history (treatment with incriminated drugs/infections/immune diseases). Typical routine stains for light microscopy include plication, and it can occur into the urine collecting results in kidney loss or death. THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 223 The diagnosis is confirmed through a kidney biopsy.  Plate 4-8 CAUSES AND PRESENTATION OF MINIMAL C Major causes EVOLUTION -Mmost INIMALpatients CHANGEmake D a ISEASE good recovery in terms of kidney function, but it is incomplete in Idiopathic 40% of Majority of cases cases (10% will eventually require Minimal change disease (MCD, also known as nil hemodialysis). disease and lipoid nephrosis) is the leading cause of nephrotic syndrome in children, accounting for 90% of Medications The Netter Collection of Medical Ilustrations: Urinary Al cases in this population, and a major cause of nephrotic NSAIDs System, Volume 5, Elsevier, Gold Second Edition, 2012. syndrome in adults. In addition to its predilection for Lithium Alpha-interferon children, MCD also occurs more frequently in Asians Ampicillin Probenecid Rifampin TREATMENT and Caucasians than in African-Americans. The name of this disease refers to the seemingly normal appearance of glomeruli when visualized using light microscopy. On electron microscopy, however, diffuse foot process effacement can be seen, which is the basis for the proteinuria. The vast majority (>85%) of MCD cases are primary, idiopathic phenomena. In the remaining cases, MCD - Discontinuing exposure to the causative drug and avoiding re-exposure are mandatory. occurs secondary to a systemic insult, such as drugs Some researchers recommend corticosteroids (methylprednisolone or oral prednisone (e.g., NSAIDs, lithium), neoplasms (especially hemato- logic malignancies), infections (e.g., tuberculosis, syphi- at 1 mg/kg/day) if renal function does not improve one lis), and allergies to common irritants (i.e., poison ivy, ragweed, poison oak, bee stings, certain foods). week after discontinuing Infections Tuberculosis M exposure, while others recommend corticosteroid therapy from the time of diagnosis. Syphilis PATHOPHYSIOLOGY Clinical features The precise mechanism of MCD is not known. One theory speculates that dysfunctional T-cells produce a cytokine called the glomerular permeability factor, which injures podocytes (visceral epithelial cells) and leads to foot process effacement. Loss of the slit dia- phragm architecture, which constitutes the normal barrier to protein filtration, leads to proteinuria. B cells may also play a role, either by producing the glomerular  CHAPTER 1 Renal Anatomy 9 CHRONIC TUBULO-INTERSTITIAL NEPHRITIS (CTI) A B Fig. 1.11 Tubules of the Renal Cortex. (A) Proximal convoluted tubule is equipped with a brush border and a prominent vacuolar apparatus in the apical cytoplasm. The rest of the cytoplasm is occupied by a basal R.J.Johnson, labyrinth consisting of large J.Floege,M.Tonelli. mitochondria associated withComprehensive clinical basolateral cell membranes. (B) Distal convoluted nephrology, tubule also Elsevier has interdigitated basolateralpublishing cell membraneshouse, 7 intimately thassociated edition, 2023. with large mitochondria. In contrast to the proximal tubule, however, the apical surface is amplied only by some stubby microvilli. (TEM; A, ×1530; B, ×1830.) reabsorption specic for the proximal tubule is the Na+-H+ exchanger of the thin limbs for the generation of the osmotic medullary gradient - CTI are a heterogeneous group of kidney disorders in which various (NHE3) that is located in the plasma membrane of the apical micro- is debated. villi and accounts for reabsorption of most of the ltered sodium. Other sodium coupled transporters in the microvillous membrane Distal Straight Tubule (Thick Ascending Limb of Henle’s Loop) are the sodium-glucose cotransporters SGLT2 and SGLT1 and several The thick ascending limb of Henle’s loop is often called the diluting etiopathogenic factors cause chronic lesions primarily affecting the tubules sodium-phosphate cotransporters. The abundance of channel protein aquaporin 1 in the apical microvillous membrane and the basolateral cell membrane accounts for the high hydraulic permeability for water segment. It is water impermeable but reabsorbs considerable amounts of sodium and chloride, resulting in the separation of salt from water. The salt is trapped in the medulla (see Fig. 1.12), whereas the water and interstitium: epithelial flattening, tubular dilation, interstitial fibrosis, and of this epithelium. An apical tubulovesicular compartment is part of is carried away into the cortex, where it may return into the systemic the prominent endosomal-lysosomal system and is responsible for the circulation. The specic transporter for Na+ reabsorption in this seg- reabsorption of macromolecules (active peptides, polypeptides, and ment is the Na+-K+-2Cl cotransporter 2 (NKCC2),39 which is speci- proteins such as albumin) that have passed the glomerular lter. cally inhibited by loop diuretics such as furosemide. This transporter is inflammatory infiltrate with mononuclear cells, possibly granulomatous, with The S3 and portions of the S2 segments are engaged in many secre- inserted in the luminal membrane, which is amplied by only solitary tory processes of toxic substances and drugs via organic anion trans- microvilli. The tight junctions of the thick ascending limb are elon- porters and an organic cation transporter (OCT). Proximal tubule cells gated by lateral interdigitation of the cells. They have a comparatively are electrically coupled by gap junctions (Nexus). low overall permeability; however, they contain the protein Claudin neutrophils and eosinophils. Intermediate Tubule The intermediate tubule includes the thin portion of Henle’s loop, thin 16 for paracellular reabsorption of divalent ions, notably of magne- sium. The cells are heavily interdigitated by basolateral cell processes, which are associated with large mitochondria supplying the energy for descending and (only in long loops) thin ascending limbs (Fig. 1.12; the transepithelial transport. The cells synthesize the Tamm-Horsfall see also Fig. 1.2). Thin descending limbs of short loops and those of protein and release it into the tubular lumen. This protein may help long loops are equipped with different epithelia. The thin descend- prevent the formation of kidney stones. A short distance before the ing limbs of short loops have an extremely at epithelium that, in its transition to the distal convoluted tubule, the thick ascending limb beginning part, is permeable to water, and, in its distal part, contains contains the macula densa, which adheres to the glomerulus of the the urea transporter UT-A2 responsible for the uptake of urea com- same nephron (see Juxtaglomerular Apparatus). ing up from the inner medulla (urea recycling).38 The thin descending limbs of long loops, in their initial parts within the inner stripe, are Distal Convoluted Tubule quite permeable to Na+ and Cl (uptake from the interstitial space) and The epithelium exhibits the most extensive basolateral interdigita- have a considerable Na+,K+-ATPase activity, the relevance of which is tion of the cells and the greatest numerical density of mitochondria unknown. Along their course down through the inner medulla they compared with all other nephron portions (see Fig. 1.11). Apically, lose their salt permeability becoming permeable to water. The tran- the cells are equipped with numerous solitary microvilli. The specic sition to the ascending thin limb epithelium occurs already before Na+ transporter of the distal convoluted tubule is the luminal Na+-Cl the bend. The ascending thin limbs have a heavily interdigitated epi- cotransport system (NCC), which can be inhibited by the thiazide thelium highly permeable for ions releasing them into the interstitial diuretics. Magnesium is reabsorbed via the transient receptor potential space but impermeable for water. The relevance of transport functions channel melastatin subtype 6 (TRPM6) in the luminal membrane40 CHRONIC TUBULO-INTERSTITIAL NEPHRITIS CHAPTER 1 Renal Anatomy 9 A B Fig. 1.11 Tubules of the Renal Cortex. (A) Proximal convoluted tubule is equipped with a brush border and a prominent vacuolar apparatus in the apical cytoplasm. The rest of the cytoplasm is occupied by a basal R.J.Johnson, J.Floege,M.Tonelli. Comprehensive clinical labyrinth consisting of large mitochondria associated with basolateral cell membranes. (B) Distal convoluted nephrology, tubule also has Elseviercell interdigitated basolateral publishing membranes intimately 7th edition, house, associated 2023. with large mitochondria. In contrast to the proximal tubule, however, the apical surface is amplied only by some stubby microvilli. (TEM; A, ×1530; B, ×1830.) reabsorption specic for the proximal tubule is the Na+-H+ exchanger of the thin limbs for the generation of the osmotic medullary gradient (NHE3) that is located in the plasma membrane of the apical micro- is debated. villi and accounts for reabsorption of most of the ltered sodium. - Progress to CKD (in 5-10% of cases), with polyuria, reduced "tubular" type Other sodium coupled transporters in the microvillous membrane Distal Straight Tubule (Thick Ascending Limb of Henle’s Loop) are the sodium-glucose cotransporters SGLT2 and SGLT1 and several The thick ascending limb of Henle’s loop is often called the diluting sodium-phosphate cotransporters. The abundance of channel protein segment. It is water impermeable but reabsorbs considerable amounts aquaporin 1 in the apical microvillous membrane and the basolateral of sodium and chloride, resulting in the separation of salt from water. proteinuria, minimal changes in urinary sediment and sometimes cell membrane accounts for the high hydraulic permeability for water of this epithelium. An apical tubulovesicular compartment is part of the prominent endosomal-lysosomal system and is responsible for the The salt is trapped in the medulla (see Fig. 1.12), whereas the water is carried away into the cortex, where it may return into the systemic circulation. The specic transporter for Na+ reabsorption in this seg- characteristic hydro-electrolytic or acid-base abnormalities, corresponding to reabsorption of macromolecules (active peptides, polypeptides, and ment is the Na+-K+-2Cl cotransporter 2 (NKCC2),39 which is speci- proteins such as albumin) that have passed the glomerular lter. cally inhibited by loop diuretics such as furosemide. This transporter is The S3 and portions of the S2 segments are engaged in many secre- inserted in the luminal membrane, which is amplied by only solitary tory processes of toxic substances and drugs via organic anion trans- microvilli. The tight junctions of the thick ascending limb are elon- the affected tubular segment. porters and an organic cation transporter (OCT). Proximal tubule cells are electrically coupled by gap junctions (Nexus). gated by lateral interdigitation of the cells. They have a comparatively low overall permeability; however, they contain the protein Claudin 16 for paracellular reabsorption of divalent ions, notably of magne- Intermediate Tubule sium. The cells are heavily interdigitated by basolateral cell processes, The intermediate tubule includes the thin portion of Henle’s loop, thin which are associated with large mitochondria supplying the energy for descending and (only in long loops) thin ascending limbs (Fig. 1.12; the transepithelial transport. The cells synthesize the Tamm-Horsfall see also Fig. 1.2). Thin descending limbs of short loops and those of protein and release it into the tubular lumen. This protein may help long loops are equipped with different epithelia. The thin descend- prevent the formation of kidney stones. A short distance before the ing limbs of short loops have an extremely at epithelium that, in its transition to the distal convoluted tubule, the thick ascending limb beginning part, is permeable to water, and, in its distal part, contains contains the macula densa, which adheres to the glomerulus of the the urea transporter UT-A2 responsible for the uptake of urea com- same nephron (see Juxtaglomerular Apparatus). ing up from the inner medulla (urea recycling).38 The thin descending limbs of long loops, in their initial parts within the inner stripe, are Distal Convoluted Tubule quite permeable to Na+ and Cl (uptake from the interstitial space) and The epithelium exhibits the most extensive basolateral interdigita- have a considerable Na+,K+-ATPase activity, the relevance of which is tion of the cells and the greatest numerical density of mitochondria unknown. Along their course down through the inner medulla they compared with all other nephron portions (see Fig. 1.11). Apically, lose their salt permeability becoming permeable to water. The tran- the cells are equipped with numerous solitary microvilli. The specic sition to the ascending thin limb epithelium occurs already before Na+ transporter of the distal convoluted tubule is the luminal Na+-Cl the bend. The ascending thin limbs have a heavily interdigitated epi- cotransport system (NCC), which can be inhibited by the thiazide thelium highly permeable for ions releasing them into the interstitial diuretics. Magnesium is reabsorbed via the transient receptor potential space but impermeable for water. The relevance of transport functions channel melastatin subtype 6 (TRPM6) in the luminal membrane40  CLASSIFICATION Analgesic nephropathy; CHRONIC TUBULO-INTERSTITIAL NEPHRITIS Drugs/toxins Balkan endemic nephropathy; Lithium-induced nephropathies Obstructive nephropathy; Obstructive (+/-infectious) Obstructive pyelonephritis; Xanthogranulomatous pyelonephritis With microcrystal deposits - uric Dysmetabolic acid, calcium phosphate/oxalate, Direct effect - hypokalemia Systemic lupus erythematosus, Sjogren's syndrome, Immunological Behcet's syndrome, Sarcoidosis, Chronic inflammatory bowel diseases Multiple myeloma, Light chain disease, Hematological diseases Amyloidosis, Malignant lymphomas, Chronic lymphocytic leukemia Autosomal dominant tubulointerstitial kidney disease; Genetic Autosomal dominant polycystic kidney disease CLINICAL FEATURES Urine examination: - reduced urine concentration capacity (urine specific gravity below 1010), polyuria with nocturia; - low-level proteinuria (below 1.5g/day), consisting of low molecular weight proteins; - poor urinary sediment or sterile pyuria, rarely isomorphic hematuria. CLINICAL FEATURES Tubular involvement: - proximal convoluted tubule (glycosuria in the absence of hyperglycemia), phosphaturia, aminoaciduria (Fanconi syndrome), proximal tubular acidosis; - distal convoluted tubule: impaired urine concentration, distal renal tubular acidosis; Interstitial involvement: - interstitial fibrosis, which may result in: anemia disproportionate to the eGFR level and progressive decline in eGFR.  Chronic Tubulointerstitial Nephritis Analgesic nephropathy - the chronic consumption of large amount of analgesic (phenacetin, but also NSAIDs) leads to chronic TIN and papillary necrosis; - more common in women, tipically at middle age; Clinical features - anaemia, CKD, haematuria or urinary tract obstruction (by affecting the renal papilla); - the abuse of analgesic could also predispose to development of uroepithelial tumours;  Analgesic nephropathy Diagnosis - long-term consumption (>5 years) of a large amount of analgesics (>3000 tablets), interstitial nephropathy (polyuria, reduced proteinuria, normal urinary sediment, slow decrease in eGFR) + non-patognomonic apperance on imaging; Management - patients should be encouraged to avoid NSAIDs - alternative drugs: dihydrocodeine or paracetamol; - the development of flank pain or an unexpectedly rapid deterioration of renal function requires a fast ultrasound examination, to screen for urinary tract obstruction due to a sloughed papilla!  Balkan nephropathy - It has a geographically restricted distribution in the valleys bordering the Danube, where 5% of inhabitants with more than 15 years of residence in the area are affected, explaining the name ”endemic nephropathy”. Pathogeny - The pathogenesis is unknown. Genetic and environmental factors are implicated. Among environmental factors, there is evidence that aristolochic acid from the plant Aristolochia clematitis (a contaminant of cereals), as well as polycyclic hydrocarbons from coal deposits located near the surface in the area (contaminants of drinking water), are potential culprits.  Balkan nephropathy Clinical Features - It affects both sexes equally. It typically begins after the age of 30 with tubular proteinuria, associated with signs of tubular dysfunction (polyuria with nocturia due to reduced urine concentration, glycosuria, aminoaciduria, acidosis). After several years, anemia and an irreversible, slowly progressive reduction of eGFR develop. It is characterized by the absence of hypertension. The appearance of hematuria indicates urothelial carcinoma. Diagnosis residence in the area for more than 15 years + There is no specific treatment. the exclusion of other nephropathies  Chinese herb nephropathy - chinese herbal medicines may contain aristolochic acid (produced as a result of fungal contamination of the product); - histology is similar to that of Balkan nephropathy but the clinical course is aggressive, with inexorable progression to ESKD; - high incidence of uroepithelial tumours.  OBSTRUCTIVE NEPHROPATHY - Prolonged obstruction of the urinary tract initially causes 710 CHAPTER 107 STRUCTURE AND FUNCTION O dilation of the urinary pathway downstream of the Corticomedullary junction Cortex Medulla The glom entering the obstruction (obstructive uropathy), followed by kidney countertran Papilla tubule cont and Na+-co damage and a decrease in eGFR (obstructive nephropathy), C alyx transported resulting in tight juncti sometimes complicated by infections (obstructive In the th cotranspor enter the ce pyelonephritis). C apsule Renal artery ing in depo convoluted - Hydronephrosis refers to the dilation of the renal pelvis Renal vein conducts N Na+, K+-AT Renal pelvis segment, th and calyces, while hydroureter and hydrocalicosis refer to Arcuate through sec In the pri artery