2283Approach to the Patient with Renal Disease or Urinary Tract Disease CHAPTER 308

well as hyperfibrinogenemia. RVT may present

with back pain or pulmonary emboli.

NS with heavy proteinuria or large kidneys on

ultrasound in advanced stages of chronic kidney

disease (CKD) is often noted in diabetic nephropathy, amyloid, HIVAN, and MN with RVT.

MN may be the presenting finding in cases of

SLE, whereas diffuse proliferative GN with low

C3, when associated with SLE, occurs in patients

who also have signs and symptoms of joint, skin,

or systemic organ involvement. A cause of very

early MN is an idiosyncratic reaction to NSAIDs,

even when taken in small amounts. Many other

drugs including penicillamine, mercury, and

gold can cause MN. Proteinuia from any cause

may present earlier, or increase, when DM,

obesity, partial nephrectomy, or increased renal

venous pressure exists.

Solid tumors, particularly lung, gastric, intestinal, bladder, breast, and prostate, may underlie

a paraneoplastic syndrome of MN. While it is

important to take a history and examine the

patient carefully for signs of cancer, it is not the

rule to work up every patient with MN exhaustively for cancer. But the neoplastic nephropathy

may be a sign of recurrent disease and may

even be recognized by tumor antigens. MN also

occurs in the context of many infectious diseases,

including syphilis, malaria, schistosomiasis, and

hepatitis B. Recently, 70% of patients with primary MN have been found to have circulating

levels of an autoantibody to the phospholipase

A2 receptor (anti-PLA2R) in the subepithelial

region of the glomerular basement membrane.

Patients who have a nephrotic and nephritic

sediment in childhood may have membranoproliferative glomerular nephritis (MPGN) with

low C3 as a primary disease (C3 glomerulopathy

or dense-deposit disease). The adult presenting

with a nephrotic and nephritic picture should be

considered to have an immune complex disorder

unless proven otherwise. In amyloidosis there

may be a simultaneous and severe tubular syndrome in addition to the albuminuria, consisting

of nephrogenic diabetes insipidus and a hyperkalemic RTA. When NS is associated with Fanconi’s

syndrome (glycosuria, phosphaturia, uricosuria,

and aminoaciduria), one must consider multiple

myeloma in the adult.

HEMATURIA AND LOWER

URINARY TRACT SYNDROMES

Because blood could enter the urinary tract from

any structure, identifying the source is a necessary

first step. As a rule, hematuria associated with

flank pain or ureteral colic is more characteristic

of a lower urinary tract source, such as a stone or

an obstructing lesion. However, when flank pain without colic is noted,

one has to consider swelling of the kidney and stretching of the renal

capsule, as might be seen in acute urinary obstruction, kidney infection,

interstitial nephritis, and, on occasion, acute glomerular nephritis. Heavy

bleeding with clots is more characteristic of lower tract bleeding but

could result from trauma to the kidney. In patients who have acute flank

pain and hypertension, assuming the pain is due to a kidney stone may

miss an occlusive vascular event from an embolus or in situ clot within

the arterial blood supply. Patients who engage in strenuous exercise may

develop hematuria that can be ruled out by retesting the urine after a

week or two of rest. True hematuria can be distinguished from hemoglobinuria and myoglobinuria by urinalysis.

Nephrotic

Syndrome

Membranoproliferative

Membranous

Focal segmental

glomerular

sclerosis

Minimal change

disease

Other

Primary

Secondary

Primary:

Idiopathic and

anti-PLA2R

Secondary

Primary

Secondary

Primary

Lymphoproliferative disorders

NSAIDs

Heroin

Adaptive injury:

obesity, DM

SLE

Malaria

Schistosomiasis

Cancer: GI,

prostate, breast,

lung, bladder

Cryoglobulins

Postinfectious

SBE

SLE

Drugs: ampicillin,

NSAIDs, gold

mercury,

penicillamine

Secondary

Diabetes

mellitus

HIV, COVID-19

Amyloidosis: AL,

SAA

FIGURE 308-3 Nephrotic syndrome. Different pathologic syndromes broken down into the idiopathic

and secondary causes. 70% of primary membranous nephropathy (MN) is associated with antibodies to

the integral subepithelial basement membrane antigen phospholipase A2

 receptor (PLA2

R). The former

term for primary membrano-proliferative GN has been replaced by pathologic syndromes involving

complement deposition (C3 glomerulopathy and dense-deposit disease in children). AL amyloid is the

form of amyloidosis secondary to lambda light-chain deposition and SAA is the protein (serum amyloid

A) associated with chronic inflammatory diseases such as rheumatoid arthritis, familial Mediterranean

fever, and tuberculosis.

in the slit diaphragm, have been shown to be responsible for most cases

of hereditary nephrotic syndrome (see Table 308-2).

In children who have a serum albumin concentration <2 g/dL,

tissue ischemia may develop, causing a “nephrotic crisis,” in which

severe abdominal pain may be mistaken for a surgical abdomen. A

20-year-old presenting with NS may have MCD, FSGS, or membranous

nephropathy (MN).

Like MCD, MN exists as primary or secondary etiology. Whereas NS

is a cause of a hypercoagulable state, particularly when it is accompanied by severe hypoalbuminemia (<2 g/dL), MN is the NS most often

associated with renal vein thrombosis (RVT) for a number of reasons,

among them the urinary loss of antithrombin-3 and plasminogen, as

2284 PART 9 Disorders of the Kidney and Urinary Tract

Symptoms of lower urinary tract disorders are dysuria, urinary

frequency, urgency, incomplete emptying, hematuria that is most

pronounced at the beginning of the stream, as well as a poor urinary

stream. Among these disorders are urinary tract infection and prostatic

hypertrophy. Hematuria of recent onset noted in the fourth decade of

life or beyond should undergo a urologic evaluation and most likely

cystoscopic examination of the bladder. However, chronic hematuric

conditions may be associated with chronic glomerular disease such as

thin basement membrane, hereditary nephritis, or IgA nephropathy.

That is why it is so important to search for previous examinations such

as insurance, military, or employment exams done in the past to determine if hematuria was present in order to establish chronicity.

ACUTE KIDNEY INJURY

Acute kidney injury (AKI) is defined by the retention of nitrogenous

solutes such as urea, uric acid, and creatinine. The creatinine concentration goes up primarily related to the amount of water absorbed

along the nephron. Because the urea but not creatinine has a reabsorptive component, the clearance of urea is less than the clearance

of creatinine. With a constant catabolic rate, a decrease in glomerular

filtration alone will affect the BUN and creatinine proportionately. In

contrast, a disorder associated with enhanced urinary concentration

(high ADH), in which urea as well as water has increased reabsorption

in the process of concentrating the urine, the retention of urea nitrogen

exceeds that of creatinine, accounting for an elevated BUN-to-creatinine ratio. Oliguric or oligoanuric states are often characterized as

prerenal, meaning preglomerular vascular disease or low perfusion

states; renal, indicating intrinsic renal disease; or postrenal, indicating

obstructive nephropathy or uropathy (see Table 308-1).

Prerenal states are often related to a decreased perfusion pressure

to the glomerular capillaries or some other interference with filtration.

The differential diagnosis includes proliferative GN (the bloodless

capillary); a preglomerular vascular disease such as scleroderma or

thrombotic microangiopathy; the use of pressors for the maintenance

of blood pressure; vasoconstrictive substances including cocaine,

iodinated IV contrast media, hemoglobin or myoglobin, and certain

antibiotics like vancomycin, cyclosporine, and tacrolimus (calcineurin

inhibitors); other vasoconstrictive drugs like nonsteroidals; and renal

nerve stimulation. Hypercalcemia and hypoxia are also vasoconstrictive. Correcting hypoxemia has a diuretic effect.

Intrinsic Renal Disease All of these will decrease perfusion pressure and decrease GFR while stimulating sodium and water reabsorption.

Therefore, the characteristic urinary findings are low urinary sodium

excretion and concentrated urine. The urine sodium concentration is usually low and the urine to plasma creatinine concentration is usually >40.

The same result could occur in bilateral renal artery stenosis, heart failure,

and other circulatory collapse. If damage is done to the renal tubules, socalled intrinsic renal disease, there may or may not be oliguria and in

fact there could be polyuria (unresponsiveness to ADH), sodium-wasting,

potassium-wasting, and acid-base disorders, each of which may predominate. One of the most frequent causes of oliguric acute renal failure is

acute tubular necrosis (ATN), caused by gram-negative sepsis, hemodynamic collapse, hemoglobinuria or myoglobinuria, and medication or

toxin ingestion. Examples are crush injury, heroin and alcohol stupor, and

compartment syndrome. Drug causes include NSAIDs, aminoglycosides,

and chemotherapeutic drugs like cisplatinum and methotrexate.

Postrenal States Postrenal states accompanied by anuria suggest

complete obstruction to the flow of urine, while polyuria and bland

urinary sediment suggest incomplete obstruction combined with

ADH unresponsiveness. The fractional excretion of sodium is usually

>1–2%, whereas in oliguric prerenal syndromes the fractional excretion of sodium is usually <1%. Exception to the low sodium excretion

would be in the case of hyperchloremic metabolic alkalosis, where

chloride is being conserved and sodium excreted with bicarbonate.

Urinary tract obstruction is usually characterized by hydronephrosis

visualized on ultrasound images or large volumes of urine removed

by bladder catheterization, indicating bladder outlet obstruction.

Exceptions to finding hydronephrosis on an imaging study include the

extrinsic obstructive compression of the kidney or ureter in retroperitoneal disease; cases in which imaging was done too soon, for example

<4 days after obstruction; or when the patient was simultaneously

obstructed and volume depleted.

As mentioned earlier, acute tubular diseases that are not primarily

due to inflammation can be caused by intratubular obstruction, from

hyperoxaluric states, or by uric acid or phosphates in tumor lysis syndrome following chemotherapy for lymphoproliferative disorders.

Other drug therapies that cause tubular injury include cisplatinum,

ifosfamide, methotrexate, aminoglycosides, and amphotericin B, and

toxicity through exposure to heavy metals.

Kidney injury in the setting of systemic disease with dysfunction

in other organs includes the cardiorenal, pulmonary renal, and

hepatorenal syndromes. Other syndromes that typically involve the

kidney include febrile illness, systemic infection with septic shock,

hemodynamic collapse due to cytokines, or capillary leak syndrome.

These syndromes as well as the endothelial origins of thrombotic

microangiopathies and hemolytic uremic syndrome are shown in

Fig. 308-4. Obstetric patients with abruptio placenta may develop bilateral cortical necrosis and as a consequence, anuria, and often irreversible renal failure. In addition, patients with atheroembolic syndrome

can present with AKI or chronic progressive damage following an aortic catheterization. If the blood vessels catheterized involve the aortic

arch, an encephalopathic syndrome that can mimic uremic encephalopathy may follow. As many as 70% of patients with COVID-19 who

required ventilators during the early phase of the pandemic developed

multiorgan failure, including AKI. AKI may also be a risk for chronic

kidney disease following a COVID-19 infection.

CHRONIC KIDNEY DISEASE AND THE

UREMIC SYNDROME

Chronic kidney disease (CKD), progressing over months to years, can

be the long-term result of any of the previously mentioned diseases.

If the time course is unknown, other ways to diagnose CKD versus

TABLE 308-2 Hereditary and Congenital Diseases

HEREDITARY

GLOMERULAR DISEASES:

NEPHROTIC SYNDROME

OR RENAL FAILURE

HEREDITARY TUBULAR

DISEASES APOL1 CILIOPATHIES CHANNELOPATHIES

CONGENITAL

ANOMALIES

Podocyte mutations;

basement membrane

mutations; hereditary

nephritis; X-linked and

somatic mutations;

COL4A5; Allport’s

syndrome with hematuria

neurosensory hearing

loss, conus lentus; Fabry’s

disease (X-linked alphagalactosidase deficiency)

Fanconi’s syndrome

with renal glycosuria,

proximal tubule RTA,

hypophosphatemia,

hypouricemia; distal RTA

with hearing loss, renal

calcification; nephrogenic

diabetes insipidus;

hyper- or hypotensive

disorders with hypo- or

hyperkalemia; metabolic

alkalosis or acidosis

Mutant allele in

African-American

population, leading to

susceptibility to further

injury in many other

disorders including

diabetes mellitus

Autosomal dominant

and recessive polycystic

kidney disease;

medullary cystic kidneys

(metabolic acidosis and

salt-wasting); other

phenotypes

Gitelman’s and Bartter’s

syndromes; disorders of

eNaC and proton pumps

Unilateral agenesis;

dysgenetic disease;

medullary sponge kidney

(hematuria, stones, or

infection); horseshoe

kidneys (proteinuria);

malposition; ureteropelvic

obstruction; cystoureteral

reflux (proteinuria)

2285Approach to the Patient with Renal Disease or Urinary Tract Disease CHAPTER 308

a more recent kidney disorder are useful, for example, the finding of

bilaterally small kidneys on a renal ultrasound. Kidneys by this method

are normally 10–12 cm in length. Small kidneys, <8 cm, are likely atrophic with irreversibly low function; but in some cases of CKD, such as

diabetes, the kidneys may be large despite kidney failure. Remarkably,

even atrophic kidneys may still produce renin to sustain blood pressure

and erythropoietin to minimize anemia; however, due to low calcitriol

in CKD, patients develop secondary hyperparathyroidism. The normal

parathyroid gland weighing 25 mg would be limited in raising PTH,

such that very elevated PTH likely is in favor of CKD. Thinning of the

renal cortex is also a sign of chronicity.

DM accounts for approximately 50% of CKD patients that progress

to end-stage renal disease (ESRD). Other important causes leading to

ESRD are IgA nephropathy, ischemic nephropathy without proteinuria

manifesting after age 50 years with hypertension, and signs of other

large-vessel disease, such as intermittent claudication from peripheral

vascular disease, stroke, and coronary artery disease. In contrast, renal

arterial disease due to fibromuscular dysplasia, seen predominantly in

white women in the fourth decade of life, does not progress to renal

failure and is a treatable form of hypertension. Other arterial diseases

include polyarteritis nodosum (PAN) and, in medium-sized vessels,

a Kawasaki-like illness affecting children, which has had a thirtyfold

increase since the onset of COVID-19 as part of the multisystem

inflammatory syndrome.

Hereditary and congenital diseases of the kidney are shown in

Table 308-2. Autosomal dominant PCKD occurs in all ethnic populations. The patient may first show signs of cysts in late teenage years

with hypertension, urinary or cyst infection, or pain and bleeding. Kidney

stones may be seen. By the age of 30 years, individuals with the disorder

will have ultrasound-detectable cysts. The clinician should know that

• Increased right

atrial pressure

• > renal vein pressure

• Decreased GFR,

increased UP

• Decreased SV, CO BP

• Systemic vasodilation,

• Increased renal

vascular resistance

• Increased salt,

water retention

• Decreased GFR

Hepatorenal Syndrome Cardiorenal Syndrome

• Postcardiac, aortic cath

• Post-anticoagulation

• CNS encephalopathy

• Cholesterol microemboli to limbs

(blue toes, livido reticularis),

pancreas, retina

• Eosinophilia

Atheroembolic Syndrome

• Increased capillary leak of protein-rich fluid to ISF

• Dx: diffuse edema, shock, non-cardiogenic shock,

 pulmonary edema

• Causes: sepsis, idiopathic, allergic, OHSS, poisonings,

toxins, IL-6, cytokines, burns

• Multi-organ failure, AKI

Capillary Leak Syndrome

• Low platelets, MAHA, schistocytes

• Low haptoglobin, high LDH

• Fibrin thrombi, endotheliosis, mesangiolysis

• HUS of childhood

• GI and bacterial toxins: Shigatoxin,

E. Coli O157:H7 (STEC)

• CNS involvement: TTP-ADAMTS13 antibodies

• Genetic: low complement C3, C4,Factors,H,I

• Antiphospholipid syndromes, ACL, anti-β2GP1

• Accelerated HBP, scleroderma

• Associated with SLE

• Pre-eclampsia

• Post-transplant syndromes

• Drugs: mitomycin, calcineurin inhibitors

Thrombotic Microangiopathies

• Long hx of aspirin, caffeine

acetaminophen, phenacetin,

or mixed APC

• Gastritis GI symptoms

• Chronic TIN

• Urothelial cancers

Analgesic Syndrome

• Goodpasture/antiGBM

• ANCA + vasculitis

• Other vasculitis

Cryoglobulinemia

SLE

IgA

Pulmonary Renal Syndrome Tumor Lysis Syndrome

• Increased SVR (SNS,

RAAS, ADH V1R)

Increased HR

• Decreased renal perfusion

pressure, RPF, GFR

• Increased Na and water

reabsorption, edema,

increased venous return

• Frank-Starling effects on CO

• Increased catabolic rate

• Encephalopathy, neuropathy

• Pericarditis

• Fluid overload, pulmonary edema, hypertension

• GI: dysgeusia, anorexia, weight loss, diarrhea

• Dry skin, pruritis

• Cell lysis-releases DNA

• 1 purine: 2 Phosphates

per dinucleotide

• Intratubular CaP

• Intratubular uric acid

obstruction

Uremic Syndrome

•

FIGURE 308-4 Categories of systemic or non-renal-based syndromes that involve the kidney and in advanced cases can cause the uremic syndrome requiring renal

replacement therapy. ACL, anticardiolipin antibodies; ADH V1R, antidiuretic hormone V1 receptor; anti-β2GP1, anti-beta-2-glycoprotein-1; APC, aspirin phenacetin caffeine;

BP, blood pressure; CaP, calcium phosphate crystals; CO, cardiac output; HUS, hemolytic uremic syndrome; IgA, immunoglobulin A; ISF, interstitial fluid; LDH, lactic

dehydrogenase; MAHA, microangiopathic hemolytic anemia; OHSS, ovarian hyperstimulation syndrome; RAAS, renin angiotensin aldosterone system; RPF, renal plasma

flow; SV, stroke volume; SNS, sympathetic nervous system; SVR systemic vascular resistance; TIN, tubulointerstitial nephritis; TTP, thrombotic thrombocytopenic purpura;

UP, urine protein.

2286 PART 9 Disorders of the Kidney and Urinary Tract

a diagnosis of PCKD requires multiple cysts in both kidneys. Cysts are

also found in the liver. The first manifestation of PCKD may be a cerebral hemorrhage, since berry aneurysms are present in a small subset

of patients with this disease, most commonly in the circle of Willis.

Hereditary nephritis with many variations includes the Alport

syndrome, involving a gene mutation (COL4A5, accounting for the

majority of cases) effecting the alpha 3 region of the noncollagenous

domain of type IV collagen in GBM. There is an X-linked pattern of

genetic transmission, where males may be most severely affected by

renal failure in middle age. The syndrome involves hematuria, neurosensory hearing loss, and ocular deformities of the lens. A predominant

symptom in hereditary nephritis is microscopic hematuria and the

pathologic correlate to this is thin basement membranes. It must be

distinguished from the less severe and more common related condition

known as thin basement membrane disease as a cause of hematuria.

Certain congenital abnormalities of the kidney, such as horseshoe

and ectopic kidneys, also shown in Table 308-2, consist of low nephron

numbers that may result in secondary FSGS. The condition known as

ureteral reflux is an abnormality involving the functional insertion of

the ureter into the muscular bladder, which normally closes off the

ureter upon bladder contraction. In reflux disease the ureter cannot

prevent retrograde flux of urine during micturition. In children this

may cause hypertension and, in some cases, secondary FSGS. Surgical

correction of the abnormality may be curative, but the child may outgrow it in adulthood in any case.

The stages of CKD are listed in Table 308-3 and are important in

terms of planning for renal replacement therapy (dialysis and transplantation), and for assessing and slowing the rate of progression,

defined as the decline in GFR over time. In CKD, the estimated GFR

(eGFR) is determined by the current stable serum creatinine, entered

into one of several equations derived from clinical trial data that

compared the subject’s value to actual measurements of GFR. For

example, the Modification of Diet in Renal Disease (MDRD) study

used a radioisotope (I125iothalamate) clearance to measure true GFR.

The equation contains additional factors such as age and sex to derive

the current eGFR, corrected for 1.73 m2

 body-surface area. This value

of eGFR is not a creatinine clearance, nor a measurement of GFR.

There has been debate about the inclusion of corrective factors that

would alter the result from that equation, based on the patient’s ethnicity and race. For example, it has been recommended in some centers to

multiply the eGFR value by a factor of 1.2 in black patients in order to

correct for the perceived underestimate of GFR using the MDRD equation. There is considerable objection to making this correction, which

may have the effect of introducing bias based on race. Because the corrected eGFR will give a higher value to the GFR, there could be delays

in discussion of renal replacement therapy and in initiation of treatment. Consequently, the correction has fallen out of favor. Recently an

alternative, the Chronic Kidney Disease Epidemiology Collaboration

(CKD-EPI), has been used that excludes race as a parameter. Another

method of calculating GFR uses cystatin-C.

In the course of CKD, the clinician must evaluate the patient for

symptoms and signs of worsening renal function. When the eGFR is

<15–20 mL/min, the patient should already have had conversations

about choices of eventual treatment and, if indicated, surgical preparation for peritoneal or hemodialysis. Attention should be given to the

sensitive topic of transition to a lifesaving but mechanical procedure. It

is also important to discuss transplantation and issues of timing. The

ethical standard is for separate clinicians to evaluate the recipient and

donor of a kidney transplant. Confidentiality and privacy are essential. Very importantly, access to transplantation has not been equally

offered to minority populations and it is incumbent on the clinician to

avoid bias by discussing the option with every patient.

Symptoms of CKD are often nonspecific and include fatigue,

weakness, loss of appetite and taste, weight loss, mood changes, and

metabolic encephalopathy that may involve cognitive changes such as

decline in executive function and the ability to calculate and remember. Other symptoms are peripheral and autonomic neuropathies and

sleep and movement disorders such as restless legs and asterixis or

myoclonus. Patients with AKD lose their ability to concentrate the

urine, and therefore have an obligate urine output of approximately

2 L. This results in nocturia, since the bladder fills during the night.

Ironically, the loss of nocturia may be sensed by the patient as an

improvement of symptoms but actually indicates worsening oliguria.

Pruritis commonly occurs. Clinical issues include changes in medications and doses. The full uremic syndrome is characterized by severe

hypertension, the above-mentioned encephalopathic manifestations,

GI bleeding, pericarditis, severe electrolyte disturbances, particularly hyperkalemia, and secondary hyperparathyroidism. Anemia is

frequently present and though it may be due to iron deficiency or

decreased erythropoietin, other causes of anemia should be investigated. Patients respond well to erythropoietic stimulating agents, with

the goal of therapy >10 g/dL but <12 g/dL. Notably, not all patients are

anemic. For example, some patients with urinary tract obstruction,

polycystic kidney disease, renal vascular disease, and renal cell carcinoma may in fact have erythrocytosis.

In nephrotic syndrome, heavy proteinuria may persist throughout

the course of CKD and carries a worse prognosis. In all kidney diseases, including the nephritic processes, renal disease may progress to

late stages even when the acute inflammation has subsided. However,

the underlying mechanisms of progressive renal failure involve inflammatory pathways (reflected in elevated levels of C-reactive protein and

erythrocyte sedimentation rate in CKD), emphasizing the importance

of managing risk factors for cardiovascular disease, such as hypertension, smoking, hyperlipidemias, diabetes, and obesity early in the

course of CKD.

Some chronic renal syndromes may present with predominant

tubular dysfunction, including genetic diseases known as channelopathies. Examples are the depletion of electrolytes such as phosphorus

and potassium and proximal RTA due to Fanconi’s syndrome, mentioned above; hypokalemic alkalosis and volume depletion in Bartter’s

syndrome (mutations resulting in abnormal loop of Henle function);

and electrolyte losses in Gitelman’s, a defect in the thiazide-sensitive

sodium-chloride transporter. Gitelman’s also causes hypochloremic

hypokalemic metabolic alkalosis. Bartter’s and Gitelman’s can be distinguished by examining the urine for the usual solutes regulated by

these transporters. Thus, Bartter’s is associated with hypercalciuria

TABLE 308-3 Stages of Chronic Kidney Disease

STAGES OF CKD,

ABNORMALITY > 3 MONTHS RANGE OF eGFR CLINICAL FEATURES IMPORTANCE

1 >60 mL/min/1.73 m2 Abnormal urinalysis, abnormal

renal imaging

Risk of progression to later stages increases with increased proteinuria

and dependent on cause of disease

2 >60 mL/min/1.73 m2 Abnormal urinalysis, abnormal

renal imaging

Mild risk of progression to later stages increases with increased

proteinuria and dependent on cause of disease

3a 45–60 mL/min/1.73 m2 Cardiovascular disease or other

organ damage

Moderate risk of progression of disease. Pay attention to other vascular

risk factors, high BP, lipids, smoking, weight

3b 30–45 mL/min/1.73 m2 Proteinuria High risk of progression

4 15–30 mL/min/1.73 m2 High likelihood of progression to ESRD, need preparation and education

regarding choices for RRT including transplant and dialysis

5 <15 mL/min/1.73 m2 Highest risk of requiring RRT

2287Cell Biology and Physiology of the Kidney CHAPTER 309

and the inability to put out a concentrated urine, whereas Gitelman’s is

associated with hypocalciuria and preserved ability to concentrate the

urine. Fanconi’s syndrome results in hypokalemic acidosis and can be

distinguished from distal RTA, which does not associate with the loss

of glucose, amino acids, and phosphate in the urine.

Disorders involving the collecting duct and its transporters of

sodium, potassium, and acid base can result in syndromes that also

suggest certain diagnoses. For example, polyuria due to inappropriate free water losses and insensitive to ADH is characteristic of

nephrogenic diabetes insipidus and it is common to see simultaneous defects in potassium secretion and hydrogen ion secretion, with

hypertension suggesting blockade of one of the sodium regulators of

ENaC. These disorders are usually associated with hyporenin and/

or hypoaldosterone states, which include UTO, type 4 RTAs in DM,

amyloidosis, or Addison’s disease. In contrast, hypokalemic metabolic

alkalosis with volume expansion may suggest an adrenal adenoma,

unilateral renal artery stenosis, ACTH-secreting tumors, licorice abuse,

or potassium-sparing diuretics.

Renal Masses Patients with renal cell carcinoma may have been

diagnosed via an incidental finding in an abdominal imaging study, or

sometimes by a palpable mass best felt with the patient supine, usually

a thin patient but occasionally a very large protruding mass. Very large

masses or multiple masses that are easily palpable may represent cystic diseases of the kidney, including polycystic kidney disease (PKD)

or even a single cyst, versus a congenital ureteral pelvic obstruction.

Other times, a renal cell carcinoma can present as anemia, possibly

caused by hematuria, or as back pain associated with metastatic lytic

vertebral lesions. Metastases may involve the lungs and the bone marrow as well.

Imaging and Renal Biopsy Indications For hematuric syndromes, imaging may add valuable information, particularly in the

patient who has heavy bleeding or blood clots in the urine. Renal

pathology may be detected as an abdominal mass, as in the case of

renal cell carcinoma, chronic urinary tract obstruction, or cystic diseases of the kidney including polycystic kidney disease (PKD) and

simple cyst. If the patient has a known history of tubular sclerosis or the

finding of skin fibroadenoma, one might identify a renal mass found

on CT imaging as an angiomyolipoma.

The renal ultrasound is efficacious in determining the size and

symmetry of the kidneys and in excluding urinary obstruction. It is

helpful in detecting renal cysts or mass, but less useful in kidney stone

disease. Ultrasound is not as accurate a tool for angiomyolipomas.

The renal-limited noncontrast CT scan is the standard test for nephrolithiasis but carries the risk of accumulative radiation. MRI is often

useful in evaluating and following renal masses, including renal cell

carcinoma. The patient with renal disease may develop the complication of systemic sclerosis after receiving gadolinium; new contrast

media to replace it are emerging. CT iodinated contrast media remain a

problem, particularly in the patient with vascular disease of the kidney.

Radioisotope scanning is useful in demonstrating the percentage of

renal function coming from each kidney. Finally, in many of the diseases discussed above, diagnosis ultimately depends on renal biopsy

and pathologic evaluation.

■ FURTHER READING

Glassock RJ: Kidney biopsy is required for nephrotic syndrome with

PLA2R+ and normal kidney function: Commentary. Kidney360

1:894, 2020.

Harding K et al: Health disparities in kidney transplantation for

African Americans. Am J Nephrol 46:165, 2017.

Levey AS et al: Nomenclature for kidney function and disease: report

of Kidney Disease: Improving Global Outcomes (KDIGO) Consensus

Conference. Kidney Int 97:1117, 2020.

Reidy KJ et al: Genetic risk of APOL1 and kidney disease in children

and young adults of African ancestry. Curr Opin Pediatr 30:252,

2018.

Ronco C: Acute kidney injury biomarkers: Are we ready for the

biomarker curve? Cardiorenal Med 9:354, 2019.

Cell Biology and

Physiology of the Kidney

Alfred L. George, Jr., Eric G. Neilson

309

The kidney is one of the most highly differentiated organs in the body.

At the conclusion of embryologic development, nearly 30 different cell

types form a multitude of filtering capillaries and segmented nephrons

enveloped by a dynamic interstitium. This cellular diversity modulates

a variety of complex physiologic processes. Endocrine functions, the

regulation of blood pressure and intraglomerular hemodynamics,

solute and water transport, acid-base balance, and removal of drug

metabolites are all accomplished by intricate mechanisms of renal

response. This breadth of physiology hinges on the clever ingenuity of

nephron architecture that evolved as complex organisms came out of

water to live on land.

EMBRYOLOGIC DEVELOPMENT

Kidneys develop from intermediate mesoderm under the timed

or sequential control of a growing number of genes, described in

Fig. 309-1. The transcription of these genes is guided by morphogenic cues that invite two ureteric buds to each penetrate bilateral

metanephric blastema, where they induce primary mesenchymal cells

to form early nephrons. The two ureteric buds emerge from posterior

nephric ducts and mature into separate collecting systems that eventually form a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal epithelial transitions to form comma-shaped

bodies at the proximal end of each ureteric bud leading to the

formation of S-shaped nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the

influence of vascular endothelial growth factor A (VEGF-A), these

penetrating cells form capillaries with surrounding mesangial cells

that differentiate into a glomerular filter for plasma water and solute.

The ureteric buds branch, and each branch produces a new set of

nephrons. The number of branching events ultimately determines

the total number of nephrons in each kidney. There are ~900,000

glomeruli in each kidney in normal-birth-weight adults and as few as

225,000 in low-birth-weight adults, with the latter producing numerous comorbid risks.

Glomeruli evolve as complex capillary filters with fenestrated endothelia under the guiding influence of VEGF-A and angiopoietin-1

secreted by adjacently developing podocytes. Epithelial podocytes

facing the urinary space envelop the exterior basement membrane supporting these emerging endothelial capillaries. Podocytes are partially

polarized and periodically slough into the urinary space by epithelialmesenchymal transition and, to a lesser extent, apoptosis, only to be

replenished by migrating parietal epithelia from Bowman capsule.

Impaired replenishment results in heavy proteinuria. Podocytes attach

to the basement membrane by special foot processes and share a slitpore membrane with their neighbor. The slit-pore membrane forms

a filter for plasma water and solute by the synthetic interaction of

nephrin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin, TRPC6,

PLCE1, and Neph 1-3 proteins. Mutations in many of these proteins

also result in heavy proteinuria. The glomerular capillaries are embedded in a mesangial matrix shrouded by parietal and proximal tubular

epithelia forming Bowman capsule. Mesangial cells have an embryonic

lineage consistent with arteriolar or juxtaglomerular cells and contain

contractile actin-myosin fibers. These mesangial cells make contact

with glomerular capillary loops, and their local matrix holds them in

condensed arrangement.

Between nephrons lies the renal interstitium. This region forms a

functional space surrounding glomeruli and their downstream tubules,

which are home to resident and trafficking cells such as fibroblasts,

dendritic cells, occasional lymphocytes, and lipid-laden macrophages.

The cortical and medullary peritubular capillaries, which siphon off

2288 PART 9 Disorders of the Kidney and Urinary Tract

solute and water following tubular reclamation of glomerular filtrate,

are also part of the interstitial fabric as well as a web of connective

tissue that supports the kidney’s emblematic architecture of folding

tubules. The relational precision of these structures determines the

unique physiology of the kidney.

Each nephron is partitioned during embryologic development

into a proximal tubule, descending and ascending limbs of the loop

of Henle, distal tubule, and the collecting duct. These classic tubular

segments build from subsegments lined by highly unique epithelia

serving regional physiology. All nephrons have the same structural

components, but there are two types whose structures depend on

their location within the kidney. The majority of nephrons are

cortical, with glomeruli located in the mid-to-outer cortex. Fewer

nephrons are juxtamedullary, with glomeruli at the boundary of the

cortex and outer medulla. Cortical nephrons have short loops of

Henle, whereas juxtamedullary nephrons have long loops of Henle.

There are critical differences in blood supply as well. The peritubular

capillaries surrounding cortical nephrons are shared among adjacent

nephrons. By contrast, juxtamedullary nephrons depend on individual capillaries called vasa recta that run alongside the long loops of

Henle. Cortical nephrons perform most of the glomerular filtration

because there are more of them and because their afferent arterioles

are larger than their respective efferent arterioles. The juxtamedullary

nephrons, with longer loops of Henle, create an osmotic gradient for

concentrating urine. How developmental instructions specify the

differentiation of all these unique epithelia among various tubular

segments is still unknown.

DETERMINANTS AND REGULATION OF

GLOMERULAR FILTRATION

Renal blood flow normally drains ~20% of the cardiac output, or

1000 mL/min. Blood reaches each nephron through the afferent arteriole leading into a glomerular capillary where ultrafiltration forms

the tubular fluid. The distal ends of the glomerular capillaries coalesce

to form an efferent arteriole leading to the first segment of a second

capillary network (cortical peritubular capillaries or medullary vasa

recta) surrounding the tubules (Fig. 309-2A). Thus, nephrons have two

capillary beds arranged in a series separated by the efferent arteriole

that regulates the hydrostatic pressure in both capillary beds. The distal

capillaries empty into small venous branches that coalesce into larger

veins to eventually form the renal vein.

The hydrostatic pressure gradient across the glomerular capillary

wall is the primary driving force for glomerular filtration. Oncotic

pressure within the capillary lumen, determined by the concentration

of unfiltered plasma proteins, partially offsets the hydrostatic pressure

gradient and opposes filtration. As the oncotic pressure rises along

the length of the glomerular capillary, the driving force for filtration

falls to zero en route to the efferent arteriole. Approximately 20% of

the renal plasma flow is filtered into Bowman space, and the ratio of

glomerular filtration rate (GFR) to renal plasma flow determines the

filtration fraction. Several factors, mostly hemodynamic, contribute to

the regulation of filtration under physiologic conditions.

Although glomerular filtration is affected by renal artery pressure,

this relationship is not linear across the range of physiologic blood

pressures due to autoregulation of GFR. Autoregulation of glomerular

filtration is the result of three major factors that modulate either afferent or efferent arteriolar tone; these include an autonomous vasoreactive (myogenic) reflex in the afferent arteriole, tubuloglomerular

feedback (TGF), and angiotensin II–mediated vasoconstriction of the

efferent arteriole. The myogenic reflex is a first line of defense against

fluctuations in renal blood flow. Acute changes in renal perfusion pressure evoke reflex constriction or dilatation of the afferent arteriole in

response to rising or falling pressure, respectively. This phenomenon

helps protect the glomerular capillary from sudden changes in systolic

pressure.

TGF changes the rate of filtration and tubular flow by reflex vasoconstriction or dilatation of the afferent arteriole. TGF is mediated

by specialized cells in the thick ascending limb of the loop of Henle

called the macula densa that act as sensors of solute concentration

and tubular fluid flow rate. With high tubular flow rates, a proxy for

an inappropriately high filtration rate, greater solute delivery to the

macula densa (Fig. 309-2B) evokes vasoconstriction of the afferent

arteriole causing GFR to return toward normal. One component of

the soluble signal from the macula densa is adenosine triphosphate

(ATP) released by the cells during increased NaCl reabsorption. ATP

is metabolized in the extracellular space to generate adenosine, a potent

vasoconstrictor of the afferent arteriole. During conditions associated

with a fall in filtration rate, a lower rate of solute delivery to the macula

densa attenuates TGF, allowing afferent arteriolar dilatation and restoring GFR to normal levels. Angiotensin II and reactive oxygen species

enhance TGF, whereas nitric oxide (NO) blunts TGF. A distinct feedback mechanism may exist between the connecting tubule and GFR

in which high Na+ delivery evokes afferent arteriolar dilation possibly

mediated by prostaglandins.

The third component underlying autoregulation of GFR involves

angiotensin II. During states of reduced renal blood flow, renin is

released from granular cells within the wall of the afferent arteriole

near the macula densa in a region called the juxtaglomerular apparatus

(Fig. 309-2B). Renin, a proteolytic enzyme, catalyzes the conversion of

angiotensinogen to angiotensin I, which is subsequently converted to

angiotensin II by angiotensin-converting enzyme (ACE) (Fig. 309-2C).

Angiotensin II evokes vasoconstriction of the efferent arteriole, and

the resulting increased glomerular hydrostatic pressure elevates GFR

to normal levels.

Pax2

Gdnf/Ret

Lhx1

Cited1

Six1

Itga8/Itgb1

Fgfr2

Hoxa11/Hoxd11

Foxd1

Slit2/Robo2

Wt1

Brn1

DII1

Jag1

Lhx1

Wnt4

Emx2

Fgf8

Notch2

Notch1

Lgr5

Nephrogenesis

Hnf1b

VEGF-A/Kdr (Flk-1) Tcf21

Foxc2

Lmx1b

Itga3/Itgb1 Pdgfb/Pdgfbr

Cxcr4/Cxcl12

Nphs1

Nck1/Nck2

Cd36

CD2AP

Neph1

Nphs2

Lamb2

Mature

glomerulus

Capillary

loop

Comma-shape S-shape

Pretubular

aggregation

Ureteric bud induction

and condensation

FIGURE 309-1 Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in the

mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney development

postulated by Saxen in 1987.

2289Cell Biology and Physiology of the Kidney CHAPTER 309

MECHANISMS OF RENAL TUBULAR

TRANSPORT

The renal tubules are composed of highly differentiated epithelia that

vary in morphology and function along the nephron (Fig. 309-3). The

cells lining the various tubular segments form monolayers connected

to one another by a specialized region of the adjacent lateral membranes called the tight junction. Tight junctions form an occlusive barrier that separates the lumen of the tubule from the interstitial spaces

surrounding the tubule and also apportions the cell membrane into

discrete domains: the apical membrane facing the tubular lumen and

the basolateral membrane facing the interstitium. This regionalization

allows cells to allocate membrane proteins and lipids asymmetrically.

Owing to this feature, renal epithelial cells are said to be polarized.

The asymmetric assignment of membrane proteins, especially proteins

mediating transport processes, provides the machinery for directional

movement of fluid and solutes by the nephron.

■ EPITHELIAL SOLUTE TRANSPORT

There are two types of epithelial transport. Movement of fluid and

solutes sequentially across the apical and basolateral cell membranes

(or vice versa) mediated by transporters, channels, or pumps is called

cellular transport. By contrast, movement of fluid and solutes through

the narrow passageway between adjacent cells is called paracellular

transport. Paracellular transport occurs through tight junctions, indicating that they are not completely “tight” or occlusive. Indeed, some

epithelial cell layers allow rather robust paracellular transport to occur

(leaky epithelia), whereas other epithelia have more restrictive tight

junctions (tight epithelia). In addition, because the ability of ions to

flow through the paracellular pathway determines the electrical resistance across the epithelial monolayer, leaky and tight epithelia are also

referred to as low- or high-resistance epithelia, respectively. The proximal tubule contains leaky epithelia, whereas distal nephron segments,

such as the collecting duct, contain tight epithelia. Leaky epithelia are

most well suited for bulk fluid reabsorption, whereas tight epithelia

allow for more refined control and regulation of transport.

■ MEMBRANE TRANSPORT

Cell membranes are composed of hydrophobic lipids that repel water

and aqueous solutes. The movement of solutes and water across cell

membranes is made possible by discrete classes of integral membrane

proteins, including channels, pumps, and transporters. These different

mechanisms mediate specific types of transport activities, including

Renin

ACE

ACE2

C

Angiotensinogen

Asp-Arg-Val-Tyr-IIe-His-Pro-Phe-His-Leu - Val-IIe-His

Angiotensin I

Asp-Arg-Val-Tyr-IIe-His-Pro-Phe - His-Leu

Angiotensin II

Asp-Arg-Val-Tyr-IIe-His-Pro-Phe

Angiotensin (I-VII)

Asp-Arg-Val-Tyr-IIe-His-Pro

Collecting

duct

B

A

Peritubular

capillaries

Distal

convoluted

tubule

Macula

densa

Renin-secreting

granular cells

Peritubular

venules

Proximal

convoluted tubule

Proximal

tubule

Bowman

capsule

Efferent

arteriole

Efferent

arteriole

Afferent

arteriole

Afferent

arteriole

Glomerulus

Glomerulus

Proximal

tubule

Thick

ascending

limb

Thick

ascending

limb

Collec

duc

Distal

convolute

tubule

Peritubular

venules

man

sule

riole

Proximal

tubule

Thic

ascend

limb

la

a

nt

le

nt

le

FIGURE 309-2 Renal microcirculation and the renin-angiotensin system. A. Diagram illustrating relationships of the nephron with glomerular and peritubular capillaries.

B. Expanded view of the glomerulus with its juxtaglomerular apparatus including the macula densa and adjacent afferent arteriole. C. Proteolytic processing steps in the

generation of angiotensins.

2290 PART 9 Disorders of the Kidney and Urinary Tract

active transport (pumps), passive transport (channels), facilitated diffusion (transporters), and secondary active transport (cotransporters).

Active transport requires metabolic energy generated by the hydrolysis

of ATP. Active transport pumps are ion-translocating ATPases, including the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases.

Active transport creates asymmetric ion concentrations across a cell

membrane and can move ions against a chemical gradient. The potential energy stored in a concentration gradient of an ion such as Na+

can be used to drive transport through other mechanisms (secondary

active transport). The movement of solutes through a membrane

protein by simple diffusion is called passive transport. This activity is

mediated by channels created by selectively permeable membrane proteins, and it allows solute or water to move across a membrane driven

by favorable concentration gradients or electrochemical potential. Facilitated diffusion is a specialized type of passive transport mediated by

simple transporters called carriers or uniporters. For example, hexose

transporters such as GLUT2 mediate glucose transport by tubular cells.

These transporters are driven by the concentration gradient for glucose that is highest in extracellular fluids and lowest in the cytoplasm

due to rapid metabolism. Many other transporters operate by translocating two or more ions/solutes in concert either in the same direction

(symporters or cotransporters) or in opposite directions (antiporters or

exchangers) across the cell membrane. The movement of two or more

ions/solutes may produce no net change in the balance of electrostatic

charges across the membrane (electroneutral), or a transport event may

alter the balance of charges (electrogenic). Several inherited disorders

of renal tubular solute and water transport occur as a consequence of

mutations in genes encoding a variety of channels, transporter proteins, and their regulators (Table 309-1).

SEGMENTAL NEPHRON FUNCTIONS

Each anatomic segment of the nephron has unique characteristics

and specialized functions enabling selective transport of solutes and

water (Fig. 309-3A). Through sequential events of reabsorption and

secretion along the nephron, tubular fluid is progressively conditioned

into urine. Knowledge of the major tubular mechanisms responsible

for solute and water transport is critical for understanding hormonal

regulation of kidney function and the pharmacologic manipulation of

renal excretion.

PROXIMAL TUBULE

The proximal tubule is responsible for reabsorbing ~60% of filtered

NaCl and water, as well as ~90% of filtered bicarbonate and most critical nutrients such as glucose and amino acids. The proximal tubule

uses both cellular and paracellular transport mechanisms. The apical

membrane of proximal tubular cells has an expanded surface area

available for reabsorption created by a dense array of microvilli called

the brush border, and leaky tight junctions enable high-capacity fluid

reabsorption.

Solute and water pass through these tight junctions to enter the

lateral intercellular space where absorption by the peritubular capillaries occurs. Bulk fluid reabsorption by the proximal tubule is

driven by high oncotic pressure and low hydrostatic pressure within

the peritubular capillaries. Cellular transport of most solutes by the

proximal tubule is coupled to the Na+ concentration gradient established by the activity of a basolateral Na+/K+-ATPase (Fig. 309-3B).

This active transport mechanism maintains a steep Na+ gradient by

keeping intracellular Na+ concentrations low. Solute reabsorption from

the tubular lumen is coupled to the Na+ gradient by Na+-dependent

Distal

convoluted

Proximal tubule

tubule

Thick ascending

limb

Cortical

collecting

duct

Connecting

tubule SGLT2

inhibitors

Loop of Henle:

MEDULLA

A

CORTEX

Thin descending

limb

Thin ascending

limb Inner medullary

collecting duct

Macula densa

Bowman

capsule

Vein

Artery

PROXIMAL TUBULE

Lumen Interstitium

HPO4 + H

H2PO4

HCO3 + H

H2CO3 H2CO3

H2O + CO2 CO2

Na

H

Na

H

H

Cl

Formate

3Na

2K

H2O

NH4

Formic

acid

carbonic

anhydrase

carbonic

anhydrase

NH3

H2O, solutes

Na

Na

Na

Amino

acids

Amino

acids

Na

HCO3

Cl

K

3Na

2K

Glucose

Phosphate

Glucose

Apical Basolateral

B

FIGURE 309-3 Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical

membrane) facing left and interstitial side (basolateral membrane) facing right. A. Overview of entire nephron. B. Proximal tubular cells. C. Typical cell in the thick ascending

limb of the loop of Henle. D. Distal convoluted tubular cell. E. Cortical collecting duct cells. F. Typical cell in the inner medullary collecting duct. The major membrane

transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of transport is indicated

by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions of hormones are illustrated by arrows with plus signs for stimulatory effects

and lines with perpendicular ends for inhibitory events. The dashed line indicates water impermeability of cell membranes in the thick ascending limb and distal convoluted

tubule.