The kidney is a structurally complex organ essential for human survival since its embryonic development. Every cell in the renal parenchyma is highly specialized in maintaining electrolyte, volume, and waste homeostasis. Renal pathologies can be grossly categorized depending on the affected segment of the nephron: the glomerulus, tubules, interstitium, or blood supply. Each one differs in clinical manifestations, making it vital for the clinician to integrate differential diagnoses. In this chapter, we will cover renal histology, kidney function, and their correlation with clinical medicine.
Macroscopically, the kidney divides into two sections: the renal cortex, the outer part of the kidney, and the medulla, the inner section. Both contain different structures of the nephron, the functional unit of the kidney. It is crucial to comprehend the nephron’s structure to understand the functioning of the kidney.
The nephron is comprised of a glomerulus and a complex tubular system. The glomerulus and the first portion of the tubular system, known as the proximal convoluted tubule (PCT), are located in the renal cortex. Following the PCT, the loop of Henle, a hairpin-like structure, penetrates the medulla and returns to the cortex to connect with the distal convoluted tubule (DCT). Finally, the nephron drains into the collecting duct via connecting tubules.
There are two types of nephrons: (1) superficial nephrons with their glomeruli located near the cortical surface and short loops of Henle, and (2) juxtamedullary nephrons, with glomeruli located near the cortico-medullary junction and long loops of Henle descending deeper into the renal medulla.
The glomerulus filters large amounts of blood, which the tubular system converts into urine through reabsorption and secretion of free water and solutes.
The glomerulus forms by a tuft of capillaries surrounded by an impervious capsule denominated Bowman’s capsule. The glomerular capillaries are flanked by two resistance vessels, the afferent and efferent arterioles, regulating intraglomerular pressure. These capillaries have unique characteristics that allow them to filter large volumes of blood. The filtration barrier is composed of three structures that provide the support and selective properties needed for the formation of the primary glomerular filtrate, the ultrafiltrate.
Once blood is filtered, the ultrafiltrate resides between the visceral epithelium and Bowman’s capsule. From here, the ultrafiltrate flows into the PCT.
The Proximal Convoluted Tubule
Bowman’s capsule gives rise to the PCT, which lies adjacent to the glomerulus in the renal cortex. The PCT forms from simple cuboidal epithelium dedicated to the absorption and transport of water, electrolytes, and other particles. These cells are characterized by a brush border of microvilli designed to increase the surface in contact with the glomerular ultrafiltrate, with abundant long, thin mitochondria lining the basal pole of the cell; and numerous vesicles involved in transcellular transport of 60 to 80% of the ultrafiltrate.
The peritubular capillaries surround the PCT. This capillary network is responsible for the blood supply of the tubules as well as the recovery of the reabsorbed free water, ions, and other plasma constituents like amino acids and glucose.
The Loop of Henle
The PCT leaves the renal cortex and turns into the thin descending limb (TDL) of the loop of Henle penetrating the renal medulla. The tubule becomes narrower, and the cells become smaller, with few mitochondria and short microvilli often unnoticeable on light microscopy.
The tubule then makes a turn upward towards the cortex, turning into the thick ascending limb (TAL). Here the lining cells become larger with more numerous microvilli and mitochondria to engage in the active transport of sodium to dilute the urine.
The Juxtaglomerular Apparatus and the Distal Convoluted Tubule
The juxtaglomerular apparatus is the region in charge of the regulation of the glomerular filtration through the tubuloglomerular feedback. Histologically, this region is near the vascular pole of the glomerulus. It is made up of the macula densa cells of the cortical TAL and the granular smooth muscle cells of the afferent arteriole of the glomerulus, functionally and structurally connected by glomerular mesangial cells. The macula densa cells are morphologically distinct tubule cells characterized by a dense region of tall cells.
The TAL turns into the DCT after returning to the renal cortex near its glomerulus of origin. The DCT comprises the nephron segment between the macula densa and the cortical collecting tubule (CCT).
The DCT cells are tall cells notable for containing the largest number of mitochondria among other cells in the nephron. They have an extensive basolateral amplification enclosing multiple mitochondria, creating a palisading appearance in the basal part of the cells. Intercalated cells begin to appear in the latter segment of the DCT and remain throughout the connecting and collecting tubules.
Connecting and collecting tubules
The final part of the nephron is the connecting tubules, where the last fine-tuning of the urine occurs. These tubules have two types of cells; the intercalated cells and the connecting tubule (CNT) cells. The intercalated cells appear dense on electron microscopy and do not have the basolateral amplification characteristic of the DCT cells. These cells regulate hydrogen and bicarbonate secretion. The connecting tubule cells also have basolateral amplification, but they possess fewer mitochondria than DCT cells.
The appearance of principal cells marks the transition into the collecting tubules and the end of the nephron. In cortical nephrons, the CNT leads to the collecting tubule, which drains to a collecting duct. The connecting tubules of juxtamedullary nephrons join and form an arcade that drains into a shared collecting duct.
The kidneys are responsible for several vital functions, including electrolyte and volume regulation, excretion of waste products, acid-base balance, synthesis of hormones such as erythropoietin, and metabolism of low molecular weight proteins.
The kidneys receive from 20 to 25% of the cardiac output; this is approximately 1,200 ml/min of renal blood flow or 600 ml/min of renal plasma flow (RPF). The filtration fraction (FF) represents the proportion of the RPF that passes into the renal tubules, and is normally 20%; this means that glomerular filtration rate (GFR) is 120 ml/min (180 L per day) in an average 60 kg person.
The GFR is the product of the Ultrafiltration Coefficient (Kf) and the net filtration pressure (the change in P),
GFR = Kf (ΔP)
where ΔP represents the sum of the Starling forces across all capillary beds and Kf is determined by the surface area available for filtration and the hydraulic conductivity of the glomerular capillary wall. Variation in any of the mentioned components may alter the GFR.
In short, filtration at a single glomerulus occurs because of four major components: (1) Kf; (2) hydraulic pressure gradient, favoring passage of water and molecules; (3) transcapillary oncotic pressure, favoring intravascular maintenance of free water and solutes; and (4) the glomerular flow rate.
The Proximal Convoluted Tubule
From the 160 to 180 L of ultrafiltrate produced per day, only 1.5 to 2 L of urine is excreted. Reabsorption of 60 to 65% of free water and NaCl occurs in the PCT. Additionally, most of the potassium, phosphate, HCO3, and nearly all nutrients, such as glucose and amino acids, are reabsorbed in this segment. The solute and water reabsorption in the proximal tubule is isotonic, with a minimum change in luminal osmolarity. This site of the nephron is also responsible for active solute secretion, hormone production, and renal gluconeogenesis.
The Loop of Henle
Reabsorption of 30 to 40% of sodium occurs in this segment with important changes in urine osmolarity. The loop of Henle divides into three segments: (1) the thin descending limb (TDL), (2) the ascending thin limb (ATL), and (3) the thick ascending limb (TAL).
The TDL is permeable to water and small solutes. In contrast, the ATL and TAL are impervious to water but permeable to solutes. The furosemide-sensitive Na+-K+-2CL- cotransporter (NKCC2) is located in the apical membrane of the TAL cells of juxtamedullary nephrons. These solutes are reabsorbed from the tubular fluid into the interstitium, increasing its osmolarity. This hypertonicity contributes to the flow of free water from the TDL into the renal interstitium. This process is known as the countercurrent mechanism. Urine becomes hypertonic as it passes through the TDL and hypotonic in the TAL, the diluting segment of the nephron. The reabsorbed water returns to the circulation along the vasa recta.
The Distal Nephron
The DCT is responsible for the fine-tuning of urine. It contributes 5 to 10% in the reabsorption of filtered sodium and chloride, as well as with K+ secretion. Just as the loop of Henle, the DCT is water-impermeable, further diluting the urine. The following cluster of transporters accomplishes solute reabsorption:
A kidney biopsy is considered the gold standard for the diagnosis, prognosis, and management of multiple diseases. Since renal diseases may be secondary to evident causes and renal biopsy is an invasive test, its indications are limited. Ultrasound-guided percutaneous renal biopsy (PRB) is the most accepted and commonly used technique to perform a renal biopsy.
The ideal sample for microscopy should contain 20 glomeruli for a native kidney biopsy and at least ten glomeruli in a transplant kidney biopsy for diagnosis. The kidney cortex contains glomeruli, and medulla primarily has tubules. Hence it is important to obtain renal cortical tissue for analysis. However, in rare circumstances, medullary tissue is useful in diagnosis like BK virus nephropathy and antibody-mediated rejection in a transplanted kidney.
After obtaining kidney tissue, it is fixed and processed with a microtome into thin sections and processed for light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM).
As previously mentioned, multiple pathologic processes can affect distinct regions of the nephron to a varying extent. As such, knowledge of the diverse lesion patterns that are observable in renal tissue through various microscopic techniques is of great importance.
There are three primary microscopy modalities of clinical relevance are light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM)
Nephron pathologies are as complex as its structure. Each specific section of the nephron is susceptible to different mechanisms of damage, for instance, glomerular diseases are often immunologically mediated, whereas tubular and interstitial disorders are more likely to be caused by toxic or infectious agents. However, more than one structure can be affected by a sole disease, as well as the interdependence of structures in the kidney makes other components be affected when only one part is damaged.
As mentioned earlier, glomerular pathologies are mostly immune. Immune disorders can be either 1) mediated by antibodies against glomerular antigens, 2) mediated by complement, or 3) pauci-immune. The clinical manifestations, as well as the microscopic appearance of the glomerulus, will be dependant on the mechanism of damage.
Diseases affecting the glomerulus generally divide into two different entities according to the clinical presentation:
Nephrotic syndrome may be primary or secondary. Primary nephrotic syndrome occurs when the kidney is the primary or sole affected organ. When systemic immunologic, metabolic, or vascular diseases affect the glomeruli, it is termed secondary nephrotic syndrome. Out of these two, secondary nephrotic syndrome is most common.
Primary Nephrotic Syndrome
The following are some of the most common causes of primary nephrotic syndrome.
Secondary Nephrotic Syndrome
Secondary nephrotic syndrome can result from systemic immunologic diseases, such as systemic lupus erythematosus or vasculitis, metabolic diseases like diabetes, or vascular diseases such as hypertension. The most common cause of secondary nephrotic syndrome is diabetes mellitus. In diabetes, hyperglycemia leads to glycosylation of vascular basement membrane, causing hyaline arteriolosclerosis. The efferent arteriole is most commonly affected, increasing the glomerular filtration pressure and hyperfiltration. This state eventually progresses to albuminuria, which is one of the first clinical markers of altered renal function. Histologically, it characteristically demonstrates mesangium sclerosis and the formation of Kimmelstiel Wilson nodules.
As with nephrotic syndrome, nephritic syndromes can also be primary or secondary. Some of the most common causes of nephritic syndrome are post-infectious glomerulonephritis, IgA nephropathy, and lupus nephritis.
A special presentation of the nephritic syndrome is the Rapidly Progressive Nephritic Syndrome. In this clinical scenario, patients progress to renal failure in weeks to months. It presents with the characteristic crescents in the Bowman space on the H&E stain. Crescents are an extra capillary proliferation of macrophages, fibroblasts, and epithelial cells, as well as the deposition of fibrin due to a rupture of the glomerular membrane, indicating a severe injury to the glomerular capillary wall. Immunofluorescence patterns help identify the etiology. The differential diagnosis is possible through histologic immunofluorescence patterns on renal biopsy.
|||Wang X,Garrett MR, Nephron number, hypertension, and CKD: physiological and genetic insight from humans and animal models. Physiological genomics. 2017 Mar 1; [PubMed PMID: 28130427]|
|||Brown AL Jr, The structure of the nephron. The Medical clinics of North America. 1966 Jul; [PubMed PMID: 5936725]|
|||McCormick JA,Ellison DH, Distal convoluted tubule. Comprehensive Physiology. 2015 Jan; [PubMed PMID: 25589264]|
|||Pollak MR,Quaggin SE,Hoenig MP,Dworkin LD, The glomerulus: the sphere of influence. Clinical journal of the American Society of Nephrology : CJASN. 2014 Aug 7; [PubMed PMID: 24875196]|
|||Bell PD,Lapointe JY,Peti-Peterdi J, Macula densa cell signaling. Annual review of physiology. 2003; [PubMed PMID: 12524458]|
|||Goligorsky MS,Iijima K,Krivenko Y,Tsukahara H,Hu Y,Moore LC, Role of mesangial cells in macula densa to afferent arteriole information transfer. Clinical and experimental pharmacology [PubMed PMID: 9248672]|
|||Subramanya AR,Ellison DH, Distal convoluted tubule. Clinical journal of the American Society of Nephrology : CJASN. 2014 Dec 5; [PubMed PMID: 24855283]|
|||Curthoys NP,Moe OW, Proximal tubule function and response to acidosis. Clinical journal of the American Society of Nephrology : CJASN. 2014 Sep 5; [PubMed PMID: 23908456]|
|||Dantzler WH,Layton AT,Layton HE,Pannabecker TL, Urine-concentrating mechanism in the inner medulla: function of the thin limbs of the loops of Henle. Clinical journal of the American Society of Nephrology : CJASN. 2014 Oct 7; [PubMed PMID: 23908457]|
|||Mount DB, Thick ascending limb of the loop of Henle. Clinical journal of the American Society of Nephrology : CJASN. 2014 Nov 7; [PubMed PMID: 25318757]|
|||Sebastian A,Hulter HN,Kurtz I,Maher T,Schambelan M, Disorders of distal nephron function. The American journal of medicine. 1982 Feb; [PubMed PMID: 6277192]|
|||Pearce D,Soundararajan R,Trimpert C,Kashlan OB,Deen PM,Kohan DE, Collecting duct principal cell transport processes and their regulation. Clinical journal of the American Society of Nephrology : CJASN. 2015 Jan 7; [PubMed PMID: 24875192]|
|||Hogan JJ,Mocanu M,Berns JS, The Native Kidney Biopsy: Update and Evidence for Best Practice. Clinical journal of the American Society of Nephrology : CJASN. 2016 Feb 5; [PubMed PMID: 26339068]|
|||Resch L,Yu W,Fraser RB,Lawen JG,Acott PD,Crocker JF,Wright JR Jr, T-cell/periodic acid-Schiff stain: a useful tool in the evaluation of tubulointerstitial infiltrates as a component of renal allograft rejection. Annals of diagnostic pathology. 2002 Apr; [PubMed PMID: 12004361]|
|||Farris AB,Alpers CE, What is the best way to measure renal fibrosis?: A pathologist's perspective. Kidney international supplements. 2014 Nov; [PubMed PMID: 26312144]|
|||Hinds IL,Gonzales L, A methenamine-silver staining technique for glomerular basement membranes in plastic-embedded renal tissue. The American journal of medical technology. 1982 Nov; [PubMed PMID: 6184992]|
|||McCloskey O,Maxwell AP, Diagnosis and management of nephrotic syndrome. The Practitioner. 2017 Feb; [PubMed PMID: 29020719]|
|||Khanna R, Clinical presentation [PubMed PMID: 21462608]|
|||Tapia C,Bashir K, Nephrotic Syndrome 2019 Jan; [PubMed PMID: 29262216]|