Physiology, Renal Blood Flow and Filtration


Article Author:
Rajeev Dalal
Zachary Bruss


Article Editor:
Jasjit Sehdev


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/15/2019 12:22:37 AM

Introduction

The kidneys function in a wide variety of ways necessary for health. They excrete metabolic waste, regulate fluid and electrolyte balance, promote bone integrity, and more. These two bean-shaped organs interact with the cardiovascular system to maintain hemodynamic stability. Renal blood flow (RBF) and glomerular filtration are important aspects of sustaining proper organ functions. A delicate balance exists between renal blood flow and the glomerular filtration rate as changes in one may affect the other. 

Function

An important interplay between RBF and proper kidney functioning is the renin-angiotensin-aldosterone system, also known as RAAS. Renin is secreted by juxtaglomerular cells in response to decreased renal arterial pressure, increased renal sympathetic activation from beta-1 adrenergic receptors, or decreased sodium delivery to macula densa cells.[1] Renin converts angiotensinogen which is made in the liver to angiotensin I. Angiotensin-converting enzyme (ACE) produced by the lungs then converts angiotensin I into angiotensin II. Angiotensin II plays many different roles. It acts on angiotensin II receptors to induce vasoconstriction and increase blood pressure. It also preferentially constricts efferent arterioles to increase the filtration when RBF is low. Angiotensin II also induces the expression of aldosterone in the adrenal cortex which increases sodium channel insertion, increases the activity of sodium/potassium pump, enhances potassium and hydrogen excretion in principal cells. These simultaneous effects act to create a gradient for sodium and water reabsorption. Another important effect of angiotensin II is to increase expression of antidiuretic hormone (ADH) in the posterior pituitary which inserts aquaporin channels on the apical membrane of principal cells for water absorption. Interestingly, it stimulates the hypothalamus to increase thirst, which may be one of the body’s mechanisms of signaling low volume states or dehydration.[2]

Mechanism

RBF originates at the hilum of the kidney through the renal artery. From the segmental artery to the interlobar artery, blood arrives parallel to the corticomedullary junction in the arcuate artery. This gives rise to the interlobular arteries that radiate toward the surface. Afferent arterioles branch off which ultimately leads into the glomerulus of Bowman’s capsule. From here, efferent arterioles begin to form the venous system and subdivide into another set of capillaries known as the peritubular capillaries. Blood then leaves the kidney and enters the venous circulation. However, efferent arterioles that are located above the corticomedullary border travel downward into the medulla. They further divide into vasa recta which surround the Loop of Henle. The purpose of these vessels is to supply capillaries located in the medulla. Differences between blood flow of the renal cortex and medulla play a significant role in the regulation of tubular osmolality. High blood flow and the peritubular capillaries in the cortex maintain a similar interstitial environment of the renal cortical tubules with that of blood plasma. However, in the medulla, the interstitial environment is different than that of blood plasma.[3] This crucial difference plays a significant role in the medullary osmotic gradient and regulation of water excretion.

RBF comprises roughly 20% of the total cardiac output; it is roughly 1 liter per minute. Flow in the kidney follows the same hemodynamic principles seen elsewhere in other organs. RBF is proportional to the difference in pressures between the renal artery and vein, but inversely proportional to the vasculature resistance. Resistance is influenced by whether a vessel is in series or in parallel. Because the kidney has vasculature that is parallel, the total resistance is decreased, thus accounting for the higher blood flow.

The glomerular filtration rate (GFR) is the amount of fluid filtered from the glomerulus into Bowman’s capsule per unit time. It indicates the condition of the kidney and can be used to help guide management in cases such as chronic kidney disease. The glomerular filtration barrier is uniquely designed to prevent the passage of certain substances according to size and charge. It is composed of an inner layer of fenestrated capillary endothelium which is freely permeable to everything except for blood cells and 100 nm or greater molecules. The middle layer is a basement membrane composed of type IV collagen and heparan sulfate. The outermost epithelial layer consists of podocyte foot processes interposed with the basement membrane. It prevents the entry of molecules greater than 50 to 60 nm. All layers contain negatively charged glycoproteins that also aid in preventing the entry of other negatively charged molecules, most notably albumin.

The GFR can be determined by the Starling equation, which is the filtration coefficient multiplied by the difference between glomerular capillary oncotic pressure and Bowman space oncotic pressure subtracted from the difference between glomerular capillary hydrostatic pressure and Bowman space hydrostatic pressure. Increases in the glomerular capillary hydrostatic pressure cause increases in net filtration pressure and GFR. However, increases in Bowman space hydrostatic pressure causes decreases in filtration pressure and GFR. This may result from ureteral constriction. Increases in protein concentration raise glomerular capillary oncotic pressure and draw in fluids through osmosis, thus decreasing GFR.

Filtration fraction (FF) is the fraction of renal plasma flow (RPF) filtered across the glomerulus. The equation is GFR divided by RPF. FF is about 20% which indicates the remaining 80% continues its pathway through the renal circulation. When the filtration fraction increases, the protein concentration of the peritubular capillaries increases. This leads to additional absorption in the proximal tubule. Instead, when the filtration fraction decreases, the amount of fluid being filtered across the glomerular filtration barrier per unit time decreases as well. The protein concentration downstream in the peritubular vessels decreases and the absorptive capacity of the proximal tubules lessens as well.

The kidneys have mechanisms designed to preserve GFR within a certain range. If GFR is too low, metabolic wastes will not get filtered from the blood into the renal tubules. If GFR is too high, the absorptive capacity of salt and water by the renal tubules becomes overwhelmed. Autoregulation manages these changes in GFR and RBF. There are two mechanisms by which this occurs. The first is called the myogenic mechanism. During the increased stretch, the renal afferent arterioles contract to decrease GFR. The second mechanism is called the tubuloglomerular feedback. These mechanisms have an important interplay as they each create individual oscillations, causing a synchronized propagating electrical signal among nephrons. [4] Increased renal arterial pressure increases the delivery of fluid and sodium to the distal nephron where the macula densa is located.[5] It senses the flow and sodium concentration. ATP is released and calcium increases in granular and smooth muscle cells of the afferent arteriole. This causes arteriole constriction and decreased renin release. This overall process helps decrease GFR and maintain it in a limited range, albeit slightly higher than baseline. If low GFR is present, there is decreased fluid flow and sodium delivery. The macula densa responds by decreasing ATP release, and there is a subsequent decrease in calcium from the smooth muscle cells of the afferent arteriole. The ensuing result is vasodilation, and increased renin release in an attempt to increase GFR. The autoregulatory pressure range is between 80 to 180 mm Hg. Outside of this range, these mechanisms mentioned above fail.

Related Testing

RPF = Clearance of para-aminohippuric acid (PAH) = [U][V] / [P]

[U] is the urine concentration of PAH in mg/mL

[V] is the urine flow rate in mL per minute

[P] is the plasma concentration of PAH in mg/mL

RBF = RPF / (1 - Hematocrit)

In this equation, the denominator denotes the amount of blood volume occupied by plasma.

Pathophysiology

The function of the kidneys is related to the cardiovascular system. Certain cardiac pathologies that cause systolic dysfunction and impaired forward flow lead to decreases in RBF. This, in turn, activates RAAS in an effort to maintain blood pressure. Long-standing activation of RAAS can lead to abnormally elevated blood pressure, excessive vasoconstriction, vascular hypertrophy, and fibrosis. It has been reported that the blockade of RAAS has been beneficial in patients with chronic systolic heart failure. Studies have shown that the administration of angiotensin II in mice models served as a protective mechanism in preventing kidney damage. [6] In certain glomerular diseases such as nephrotic syndrome, anionic glycoproteins in the filtration barrier may be removed, decreasing the selective charge and resulting in proteinuria. Another aspect that regulates renal blood flow is the renal afferent and efferent nerves. When sympathetic activity is increased, it contributes to renal hypertension and end-stage renal disease. Studies have shown that catheter-based sympathetic denervation improved blood pressure.[7]

Clinical Significance

Changes in glomerular dynamics are important factors for clinicians to consider when evaluating the effects of diverse pathologies on the kidney. Afferent arteriole constriction leads to decreased GFR and decreased RPF, resulting in no change in FF. One important function of prostaglandins is to dilate the afferent arteriole. Thus when non-steroidal anti-inflammatory drugs (NSAID) are administered to patients, these changes in the glomerulus are to be expected because NSAIDs reduce the formation of prostaglandins.[8] Thus, in a patient exhibiting signs and symptoms of kidney disease, clinicians should take caution in prescribing NSAIDs. During efferent arteriole constriction, GFR is increased, but RPF is decreased, resulting in increased filtration fraction. During a state of increased plasma protein concentration such as during multiple myeloma, GFR is decreased with no change in RPF, resulting in decreased FF. However, during a state of decreased plasma protein concentration such as during nephrotic syndrome, GFR is increased with no change in RPF, resulting in increased FF. Constriction of a ureter such as during nephrolithiasis may lead to decreased GFR with no change in RPF, resulting in decreased FF. Finally, during low-volume states as in dehydration, GFR is decreased, but RPF is decreased to a much larger extent. This results in an increased FF.

One of the most commonly used medications for patients with diabetes or heart failure is an ACE inhibitor. It reduces the formation of angiotensin II, which in turn decreases GFR by preventing the constriction of efferent arterioles. Because ACE inactivates bradykinin, a potent vasodilator, a side effect of using an ACE inhibitor is angioedema from increased bradykinin levels. Another common adverse reaction is a cough. Patients with intolerance should be switched to angiotensin II receptors blockers (ARBs).

In patients with chronic kidney disease undergoing anesthesia, care should be taken to maintain renal perfusion pressures as certain agents are known to decrease the GFR and cause renal injury such as methoxyflurane.[9] Additionally, the dosage of anesthetic medications should be carefully titrated in patients with renal failure. For instance, vecuronium has an active metabolite that may prolong the duration of the dose in renal failure and should be adjusted to minimize adverse effects.[10]


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Physiology, Renal Blood Flow and Filtration - Questions

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A 52-year-old obese female presents to the clinic for diabetes and hypertension management. Her most recent glomerular filtration rate (GFR) is 41 ml/min/1.73m2, which is a significant decline in her renal function since her last GFR measured three months prior to being 74 ml/min/1.73m2. Concerned for the patient's declining kidney function, the physician elects to prescribe her lisinopril. What effect will this have on the GFR and renal blood flow (RBF)?



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Following a prolonged delivery, a 16-year-old primigravid female with no history of prenatal care delivers a baby boy. One minute Apgar score is 6 and at 3 minutes the neonatologist suspects the neonate to have an underlying congenital heart defect given his significant cyanosis and respiratory distress. Alprostadil is administered and the neonate is rushed off for emergent atrial septostomy. As the medication is being administered which of the following physiologic changes is expected to occur in the kidneys because of the drug?



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A 53-year-old male presents to the emergency department complaining of severe watery diarrhea. He returned from a medical mission trip two days ago where the village he was working experienced an outbreak of Cholera. The patient mentions he was very meticulous with boiling the water that he drank and washing all the food that he ate. Rapid cholera dipstick is positive and the patient is started on IV fluids. Prior to IV fluid resuscitation, which part of the patient's body is most active in the resorption of water?



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Which of the following is not a component of the glomerular filtration barrier?



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A 43-year-old male presents to his physician for a well-check visit after not seeing a physician in over 5 years. His blood pressure on arrival was 152/94 mmHg and 147/91 mmHg ten minutes later. The patient states that he has not been eating healthy over the last month, consuming a lot of processed foods high in sodium. Compared to one month ago, which of the following medications listed would display a similar change in renin concentration to that of the patient today?



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An 86-year-old male was begrudgingly brought to the clinic by his daughter-in-law after his continuous complaints of fatigue ongoing the past few months. He denies a medical history but has refused to see a physician in over 20 years since his wife passed away following an appendectomy that had gone awry. Aside from the fatigue, his only complaints are mild back pain and stomach pain, which has occurred on and off for years for which he takes non-steroidal anti-inflammatory drugs (NSAIDs) with some relief. Physical examination is significant for mild epigastric tenderness to palpation and + 1 pedal edema of the lower extremities bilaterally. Testing of para-amino hippuric acid clearance (a conjugate measure for renal plasma flow) and glomerular filtration rate (GFR) on lab results helped the physician conclude that the patient’s disease involved a significant decrease in the renal filtration fraction. Which of the following study results is diagnostic of this patient’s underlying disease.



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A 63-year-old male presents with shortness of breath for the past 3 days. Physical exam reveals bibasilar crackles and pulmonary edema. He has been hospitalized in the past with similar symptoms. Past medical history is significant for hypertension, hyperlipidemia, congestive heart failure, and coronary artery disease. He smoked 1 pack per day for 25 years before quitting 3 years ago. His temperature is 98.6 F, pulse 96 bpm, respiratory rate 21/minute, and oxygen saturation is 94%. An echocardiogram shows an ejection fraction (EF) of 38%. Congestive heart failure exacerbation is suspected. Which of the following is expected in the kidneys?



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A 3-year-old male presents with bilateral swollen legs. When admitted to the hospital, a workup reveals hyperlipidemia and urinary protein excretion rate of 4.5 grams within 24 hours. Which of the following is expected in the changes of glomerular dynamics?



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A 53-year-old woman who is known case history of chronic kidney disease (CKD) presents to the hospital for her regular follow up appointment. Laboratory analysis in the post-absorptive period reveals a low plasma histidine level but high histamine. Which region within the kidney is being affected most by this finding?



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A 45-year-old man has a severe allergic reaction in the community and is treated in the emergency department with an IM injection. What physiologic effects would this drug have on the kidney?



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Physiology, Renal Blood Flow and Filtration - References

References

Bichet DG, Vasopressin and the Regulation of Thirst. Annals of nutrition & metabolism. 2018     [PubMed]
Papinska AM,Rodgers KE, Long-Term Administration of Angiotensin (1-7) to {i}db/db{/i} Mice Reduces Oxidative Stress Damage in the Kidneys and Prevents Renal Dysfunction. Oxidative medicine and cellular longevity. 2018     [PubMed]
Ames MK,Atkins CE,Pitt B, The renin-angiotensin-aldosterone system and its suppression. Journal of veterinary internal medicine. 2019 Feb 26     [PubMed]
Pallone TL,Edwards A,Mattson DL, Renal medullary circulation. Comprehensive Physiology. 2012 Jan     [PubMed]
Marsh DJ,Postnov DD,Sosnovtseva OV,Holstein-Rathlou NH, The nephron-arterial network and its interactions. American journal of physiology. Renal physiology. 2019 Feb 13     [PubMed]
Wang H,Romero CA,Masjoan Juncos JX,Monu SR,Peterson EL,Carretero OA, Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF). American journal of physiology. Renal physiology. 2017 Dec 1     [PubMed]
Sata Y,Head GA,Denton K,May CN,Schlaich MP, Role of the Sympathetic Nervous System and Its Modulation in Renal Hypertension. Frontiers in medicine. 2018     [PubMed]
Rotunno R,Oppo I,Saetta G,Aveta P,Bruno S, NSAIDs and heart failure: A dangerous relationship. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace. 2018 Jun 7     [PubMed]
Dayan AD, Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity. Human & experimental toxicology. 2016 Jan     [PubMed]
Tarbeeh GA,Othman MM, The pharmacodynamics of vecuronium in chronic renal failure patients: the impact of different priming doses. Renal failure. 2012     [PubMed]

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