General Concept: Clinical Presentation and Laboratory

Diagnosis in Nephrology

Yu-Juei Hsu

Current Medical Diagnosis & Treatment 2019

Kidney Disease

Introductions 慢性腎臟病變---概念圖

Self recovery傷害因子

S

O

Hx

PE

LabUrine

Blood腎臟基本檢驗及檢查

診斷

解剖

生理

病生理

疾病(症狀)

求診

Clinical presentation

腎元

認識腎臟 — 解剖構造

每個腎臟有一百萬個腎元

腎絲球

腎小管

每日體內代謝產生的廢物會進入血液中，由腎臟來負責過濾血液中的含氮廢物與過多的液體。

腎臟每天過濾液體約160-190公升，其中大部份皆回收體內，僅約1-2公升離開身體形成尿液。

Introductions

分泌尿液、排出代謝產物、藥物及廢物腎功能

調節體內體液、電解質及酸鹼平衡水分、電解質異常代謝性酸鹼中毒

荷爾蒙之分泌紅血球生成素 (Erythropoietin)

維生素D (Vitamin D3)

腎素（Renin）

Introductions

腎臟位置圖

腎臟病生理學•腎絲球疾病（chapter 264）•腎小管疾病（chapter 265）•腎間質疾病（chapter 266）•腎血管疾病（chapter 267）•電解質、酸鹼平衡

腎衰竭

急性（chapter 260）慢性（chapter 261）透析（chapter 262）移植（chapter 263）

鈉：鈉及水鉀代謝性酸中毒代謝性鹼中毒

(chapter 41)

(chapter 42)Harrison Textbook 16th ed. 2004

URINE ANALYSIS

Reference Range

•Color – Yellow (light/pale to dark/deep amber)•Clarity/turbidity – Clear or cloudy•pH – 4.5-8•Specific gravity – 1.005-1.025•Glucose - ≤130 mg/d•Ketones – None•Nitrites – Negative•Leukocyte esterase – Negative•Bilirubin – Negative•Urobilirubin – Small amount (0.5-1 mg/dL)•Blood - ≤3 RBCs•Protein - ≤150 mg/d•RBCs - ≤2 RBCs/hpf•WBCs - ≤2-5 WBCs/hpf•Squamous epithelial cells - ≤15-20 squamous epithelial cells/hpf•Casts – 0-5 hyaline casts/lpf•Crystals – Occasionally•Bacteria – None•Yeast - None

Specific Gravity (1.002 – 1.035)

• Specific gravity of urine is a measure of the amount of solutes dissolved in urine as compared to water (1.000).

• Specific Gravity measures the ability of the kidney to concentrate or dilute the urine and is directly proportional to urine osmolality (solute concentration).

• Specific gravity between 1.002 and 1.035 on a random sample is normal IF kidney function is normal.

• Decreased: <1.005• Inability to concentrate urine or excessive hydration (volume resuscitation with IV fluids)

• Nephrogenic diabetes insipidus, acute golmerulonephritis, pyelonephritis, acute tubular necrosis

• Note: If specific gravity is not > 1.022 after a 12 hour period without food or water, renal concentrating ability is impaired and the patient either has generalized renal impairment or nephrogenic diabetes insipidus.

• Falsely low specific gravity can be associated with alkaline urine

• Fixed: 1.010• The glomerular filtrate in Bowman’s space ranges from 1.007 to 1.010, any measurement below this range indicates hydration and any measurement above it indicates

relative dehydration

• In end stage renal disease, specific gravity tends towards 1.010.

• Chronic Renal Failure (CRF), Chronic glomerulonephritis (GN)

• Increased: >1.035• Increased specific gravity indicates a concentrated urine with a large volume of dissolved solutes

• Dehydration (fever, vomiting, diarrohea), SIADH, adrenal insufficiency, pre-renal renal failure, hyponatraemia with oedema, liver failure, CCF, nephrotic syndrome

• Elevation in specific gravity also occurs with glycosuria (e.g. diabetes mellitus or IV glucose administration), proteinuria, IV contrast, urine contamination, LMW dextran solutions (colloid)

pH (4.5-8.0)

• The kidneys play an important role in acid-base regulation within the body to maintain a normal urinary pH range between 5.5 –6.5 but it may vary from as low as 4.5 to as high as 8.0.

• The glomerular filtrate of blood plasma is usually acidified by renal tubules and collecting ducts from a pH of 7.4 to about 6 in the final urine.

• Control of pH is important in the management of several diseases, including bacteriuria, renal calculi, and drug therapy.

• High Urinary pH (Alkali Urine)• Vegetarian diet, low carbohydrate diet or ingestion of citrus fruit (although citrus fruits are acidic – the digestion process leaves an alkali ash)• Systemic alkalosis (metabolic or respiratory)• Renal tubular acidosis (RTA I (distal)), Fanconi syndrome• Urinary tract infections (Bacteruria with urea splitting organisms)• Drugs: Amphotercin B, carbonic anhydrase inhibitors (acetazolomide), NaHCO3, salicylate OD• Stale ammoniacal sample (left standing)

• Low Urinary pH (Acidic urine)• High protein diet or fruits such as cranberries• Systemic acidosis (metabolic or respiratory)• Diabetes mellitus, starvation, diarrhoea, malabsorption• Phenylketonuria, alkaptonuria, renal tuberculosis

Protein

• Normal daily protein excretion should not exceed 150mg/24 hours or 10mg/100mL. Proteinuria is defined by the production of >150mg/day with nephtoric syndrome producing >3.5g/day

• Dipstick urinalysis detects protein with Bromphenol blue indicator dye and is most sensitive to albumin and less sensitive to Bence-Jones protein and globulins. Trace positive results are equivalent to 10 mg/100 ml or about 150 mg/24 hours (the upper limit of normal).

• True protein elevation:• Renal: Increased renal tubular secretion,increased glomerular filtration (glomerular disease), nephrotic syndrome,

pyelonephritis, glomerulonephritis, malignant hypertension• CVS: Benign HT, CCF, SBE• Functional proteinuria (albuminuria): fever, cold exposure, stress, pregnancy, eclampsia, CHF, shock, severe exercise• Other: Orthostatic proteinuria, electric current injury, hypokalaemia, Cushing’s syndrome• Drugs: Aminoglycosides, gold, amphotericin, NSAID, sulphonamides, penicillins

• Note: Bence Jones globulin associated with multiple myeloma, lymphoma and macroglobulinaemiais NOT detected by dipstick urinalysis

• False Positive: Concentrated urine (UO<2.5L/day), alkaline urine (pH >7.5), trace residue of bleach, aceazolomide, cephalosporins, NaHCO3

• False Negative: Dilute urine (UO >5.0 litres/day) or acidic urine (pH <5)

DipstickProtein reading Protein excretion gm/24 hours

Protein excretion mg/dL

Negative <0.1 <10

Trace 0.1-0.2 15

1+ 0.2-0.5 30

2+ 0.5-1.5 100

3+ 2.0-5.0 300

4+ >5.0 >1000

Leucocytes (White cell count)

• Determines the presence of whole or lysed white cells in the urine (pyuria) by detecting leucocyte esterase activity.

• A positive leucocyte esterase test correlates well with pyuria. However, the diagnosis may be missed in up to 20% of cases if a negative urinalysis dipstick is used to exclude UTI.• False positive: Contaminated specimen, trichomonas vaginalis, drugs or foods

that colour the urine red

• False negative: Intercurrent or recent antibiotic therapy (especially gentamicin, tetracycline and cephalosporins), glycosuria, proteinuria, high specific gravity. Low bacteria count UTI (especially in women)

Nitrites

• Nitrates in the urine are converted to nitrites in the presence of Gram-negative bacteria such as E.coli and Klebsiella.

• A positive nitrite test is a surrogate marker of bacteruria.

• Positive test strongly suggests infection but negative test does not exclude it (PPV 95% and NPV 25-70%)• False negative: Drugs or foods that colour the urine red. Certain bacteria such

as S. saprophyticus, acinetobacter and most enterococci

Blood

• Dipstick urinalysis is able to detect haemolysed and non-haemolysed blood in the urine.

• The pseudoperoxidase reaction of erythrocytes, free haemoglobin or myoglobin catalyses chromogen oxidation on the dipstick to produce a colour change.

• A positive result may be indicative of haematuria from trauma, infection, inflammation, infarction, calculi, neoplasia, clotting disorders or chronic infection (see haematuria chapter)

• Haemaglobinuria may be associated with intravascular haemolysis, burns, sudden cold, eclampsia, sickle cell crisis, multiple myeloma, alkaloids (mushrooms) and transfusion reactions

Ketones

• Ketones (acetone, aceto-acetic acid, beta-hydroxybutyric acid) are the end-point of incomplete fat metabolism. They accumulate in the plasma and are excreted in urine.

• Ketonuria is associated with low carbohydrate (high fat/protein) diets, starvation, diabetes, alcoholism, eclampsia and hyperthyroidism.

• Ketonuria also associated with overdose of insulin, isoniazid and isopropyl alcohol.

• Most urinalysis reagent tests utilise the nitroprusside test which is most sensitive to aceto-acetic acid, less sensitive to acetone, and not sensitive to beta-hydroxybutyric acid• False positive: Heavily pigmented urine. Drugs such as captopril, L-dopa, salicylates,

phenothiazines.• False negative: Negative nitroprusside tests for ketonuria underestimate the

presence of ketonemia due to increased beta-hydroxybutyric acid concentrations

Glucose

• Glucose is not normally present in the urine with < 0.1% of glucose normally filtered by the glomerulus appears in urine (< 130 mg/24 hr).

• Glycosuria occurs in patients with elevated serum glucose levels (e.g. diabetes mellitus see chapter on hyperglycaemia) or in the presence of a reduced renal threshold and reduced glucose reabsorption in renal tubular disease and pregnancy.

• Glycosuria also associated with certain drugs such as cephalosporins, penicillins, nitrofurantoin, methyldopa, tetracycline, lithium, carbemazepine, phenothiazines, steroids and thiazides• False positive: Hydrogen peroxide or bleach• False negative: Ascorbic acid (vitamin C) or fruit juices. Some dipsticks are affected

by increased specific gravity and ketonuria.

Bilirubin

• Bilirubin is not present in the urine of normal healthy individuals. The presence of bilirubinuriamay be an early indicator of liver disease and occur befor the clinical signs of jaundice develop.

• Bilirubin is formed as a by-product of red blood cell degradation in the liver, and then conjugated with the solubilising sugar, glucuronic acid and excreted in bile. Within the intestine, the bilirubin is converted into stercobilin (exrcreted in faeces) and urobilinogen (excreted by the kidneys).

• Failure of conjugated bilrubin to reach the intestines (e.g. biliary obstruction) will result in bilirubinuria. Note: Only conjugated bilrubin can be excreted as bilirubinuria. A positive test for urine bilirbin confirms conjugated hyperbilirubinaemia. (Reference)

• Raised conjugated bilirubinaemia (with bilirubinuria) is associated with hepatocellular disease, cirrhosis, viral and drug induced hepatitis, biliary tract obstruction (e.g. choledocholithiasis), pancreatic causes of obstructive jaundice (e.g. carcinoma of the head of the pancreas) and recurrent idiopathic jaundice of pregnancy

• False positive: Phenothiazines• False negative: Ascorbic acid (vitamin C), aged sample (conjugated bilirubin hydrolses to unconjugated

bilirubin at room temperature), rifampicin and exposure to UV light (converts bilrubin to biliverdin)

Urobilinogen

• Urobilinogen is normally present in the urine in low concentrations (0.2-1.0 mg/dL or <17 micromol/L). Bilirubin is converted to urobilinogen by intestinal bacteria in the duodenum. Most urobilinogen is excreted in the faeces or transported back to the liver and converted into bile. The remaining urobilinogen (<1%) is excreted in the urine.

• Urobilinogen is present in increased concentrations in the urine in patients with cirrhosis, infective hepatitis, extravascular haemolysis, haemolyticanaemia, pernicious anaemia, malaria, and hepatitis secondary to infectious mononucleosis

• Very sensitive but non-specific test to determine liver damage, haemolyticdisease and severe infections. Urobilinogen levels are decreased or absent in obstructive jaundice and elevated levels of bilirubinuria

Dipstick Urinalysis

Normal Biliary obstruction

Hepatic disease Haemolytic disease

Bilirubin Negative Positive Positive Negative

Urobilinogen Positive Negative/ Decreased

Increased Increased

Urinary casts (phase contrast microscopy). (A), Hyaline cast; (B), hyaline-granular cast; (C), waxy cast; (D), erythrocyte cast, with erythrocytes (arrows) embedded in cast matrix; (E), hemoglobin cast; (F), leukocyte cast, showing large nuclei (arrows) characteristic of polymorphonuclear leukocytes.

Type Significance

Hyaline casts Concentrated urine, febrile disease, after strenuous exercise, during diuretic therapy (not indicative of kidney disease)

Red cell casts Glomerulonephritis

White cell casts Pyelonephritis, interstitial nephritis (indicative of infection or inflammation)

Renal tubular cell casts Acute tubular necrosis, interstitial nephritis

Coarse, granular casts Nonspecific; can represent acute tubular necrosis

Broad, waxy casts Chronic kidney disease (indicative of stasis in enlarged collecting tubules)

Significance of specific urinary casts

BLOOD

Blood Urea Nitrogen (BUN)

• Urea or BUN is a nitrogen-containing compound formed in the liver as the end product or protein metabolism and urea cycle. About 85% of urea is eliminated via kidneys; the rest is excreted via the gastrointestinal (GI) tract. Serum urea is increased in conditions where renal clearance decreased (in acute and chronic renal failure/impairment). Urea may also increase in other conditions not related to renal diseases such as upper GI bleeding, dehydration, catabolic states, and high protein diets. Urea may be decreased in starvation, low-protein diet, and severe liver disease. Serum creatinine is a more accurate assessment of renal function than urea; however, urea is increased earlier in renal disease.

• The ratio of BUN: Creatinine can be useful to differentiate prerenal from renal causes when the BUN is increased. In pre-renal disease the ratio is close to 20:1, while in intrinsic renal disease it is closer to 10:1.

Creatinine

• The most commonly used endogenous marker for assessment of glomerular function is creatinine. The calculated clearance of creatinine is used to provide an indicator of GFR. This involves the collection of urine over a 24-hour period or preferably over an accurately timed period of 5 to 8 hours since 24-hour collections are notoriously unreliable. Creatinine clearance is then calculated using the equation:

• C = (U x V) / P

• C = clearance, U = urinary concentration, V = urinary flow rate (volume/time ie ml/min), and P = plasma concentration

Cystatin C

• Cystatin C is a low-molecular-weight protein which functions as a protease inhibitor produced by all nucleated cells in the body. It is formed at a constant rate and freely filtered by the kidneys. Serum levels of cystatin C are inversely correlated with the glomerular filtration rate (GFR). In other words, high values indicate low GFRs, while lower values indicate higher GFRs, similar to creatinine. The renal handling of cystatin C differs from creatinine. While both are freely filtered by glomeruli, once cystatin C is filtered, it is reabsorbed and metabolized by proximal renal tubules, unlike creatinine. Thus, under normal conditions, cystatin C does not enter the final excreted urine to any significant degree. Cystatin C is measured in serum and urine. The advantages of cystatin C over creatinine are that it is not affected by age, muscle bulk, or diet, and various reports have indicated that it is a more reliable marker of GFR than creatinine particularly in early renal impairment. Cystatin C has also be incorporated into eGFR equations such as the combined creatinine-cystatin KDIGO CKD-EPI equation. Cystatin C concentration may be affected by the presence of cancer, thyroid disease, and smoking.

IMAGING STUDIES

Ultrasonography

• Ultrasonography can characterize the thickness and echogenicity of the renal cortex, medulla, and pyramids and identify a distended urine collecting system. Kidney size can be measured; normal kidney size, which can vary depending on age and size of adults, is usually 9–12 cm in length. A kidney less than 9 cm in length in an adult suggests (but does not confirm) significant, irreversible kidney disease. A difference in size of more than 1.5 cm between the two kidneys may be observed in unilateral kidney disease. Kidney ultrasound is also performed to assess for obstruction and hydronephrosis (eFigure 22–2), to characterize kidney mass lesions, to screen for autosomal dominant polycystic kidney disease (see Figure 22–6), to evaluate the perirenal space, to localize the kidney for a percutaneous invasive procedure, and to assess postvoiding residual urine volume of the bladder. Assessing kidneys in markedly obese patients can be difficult due to body habitus; a CT scan may be required.

CT Scanning

• CT scanning may be required to further investigate abnormalities detected by ultrasonography. Although routine CT requires radiographic contrast administration, no contrast is necessary if the study is performed to identify renal parenchymal hemorrhage or calcifications in suspected kidney stone disease (nephrolithiasis). Noncontrast helical CT scanning is 95% sensitive and 98% specific for diagnosing nephrolithiasis in patients with acute flank pain, and is considered the test of choice in diagnosis of nephrolithiasis. Because contrast is filtered by the glomeruli and concentrated in the tubules, there is enhancement of parenchymal tissue, making abnormalities such as cysts or neoplasms easily identified and allowing good visualization of renal vessels and ureters. CT scanning is especially useful for evaluation of solid or cystic lesions in the kidney or the retroperitoneal space, particularly if ultrasound results are suboptimal.

MRI Scanning

• MRI can easily distinguish renal cortex from medulla. Loss of the corticomedullary junction in a variety of disorders (eg, glomerulonephritis, hydronephrosis, renal vascular occlusion, and renal failure) is evident on MRI. Renal cysts can also be identified by MRI. For some solid lesions, MRI may be superior to CT scans. MRI is indicated as an addition or alternative to CT scanning for staging renal cell cancer and as a substitute for CT scanning in the evaluation of a renal mass, especially for patients in whom iodinated contrast is contraindicated; in addition, the adrenals are well imaged. The use of gadolinium contrast in MRI, however, is contraindicated in patients with CKD stage 4 or 5, AKI, or a kidney transplant due to the risk of nephrogenic systemic fibrosis. MRI is nearly 100% sensitive and 96–98% specific for the diagnosis of renal artery stenosis.

Radionuclide Studies

• Radionuclide studies can measure kidney function. The indications for nuclear renography are to measure function and flow, to determine the contribution of each kidney to overall kidney function, to demonstrate the presence or absence of functioning kidney tissue in mass lesions, to detect obstruction, and to evaluate renovascular disease. [125I] Iothalamate gives an accurate measurement of GFR. It is injected intravenously, excreted renally, and sampled from the venous circulation over time. Technetium-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) is freely filtered by the glomerulus, not reabsorbed and is also used to estimate GFR. Technetium labeled dimercaptosuccinicacid (99mTc-DMSA) is bound to the tubules and provides an assessment of functional renal mass. [131I]Orthoiodohippurate is secreted into the renal tubules and assesses renal plasma flow.

• Poor flow along with poor function is consistent with ATN or ESRD. Decreased flow to one kidney suggests arterial occlusion of that kidney. To further investigate renal artery stenosis, the test is done both with and without captopril ; however, CT scanning and MRI are the preferred imaging modalities when assessing renal artery stenosis.

Intravenous Urography

• The intravenous pyelogram (IVP) had been the standard imaging procedure for evaluating the urinary tract because it provides an assessment of the kidneys, ureters, and bladder. An IVP necessitates the injection of contrast, however, and is relatively contraindicated in patients at increased risk for AKI (eg, diabetes mellitus with serum creatinine greater than 2 mg/dL, severe volume depletion, or prerenal azotemia), CKD, and plasma cell myeloma. It is still useful in diagnosing certain disorders such as medullary sponge kidney and papillary necrosis. Ultrasonography often replaces IVP to avoid dye administration, and helical CT scanning often replaces IVP for stone evaluation.

Arteriography & Venography

• Renal arteriography is useful in the evaluation of atherosclerotic or fibrodysplastic stenotic lesions, aneurysms, vasculitis, and renal mass lesions. Venography is the best test for diagnosis of renal vein thrombosis, though CT scanning and MRI are less invasive for this purpose.

KIDNEY BIOPSY

• Indications for percutaneous needle biopsy include (1) unexplained AKI or CKD; (2) unexplained proteinuria and hematuria; (3) previously identified and treated lesions to guide future therapy; (4) systemic diseases associated with kidney dysfunction, such as systemic lupus erythematosus (SLE), anti-GBM disease (Goodpasture syndrome), and granulomatosis with polyangiitis, to confirm the extent of renal involvement and to guide management; and (5) suspected kidney transplant rejection, to differentiate it from other causes of AKI. If a patient is unwilling to accept therapy based on biopsy findings, the risk of biopsy may outweigh its benefit. Relative contraindications include a solitary or ectopic kidney (exception: transplant allografts), horseshoe kidney, ESRD, congenital anomalies, and multiple cysts. Absolute contraindications include an uncorrected bleeding disorder, severe uncontrolled hypertension, renal infection, renal neoplasm, hydronephrosis, or an uncooperative patient.

Differential Diagnosis

• Glomerular

• Tubular

• Interstitial

• Vascular

Typical PresentationAssociation/Notes Serology

Postinfectious glomerulonephritis Children: abrupt onset of nephritic syndrome and acute kidney injury but can present anywhere in nephritic spectrum

Streptococci, other bacterial infections (eg, staphylococci, endocarditis, shunt infections)

Rising ASO titers, low complement levels

IgA nephropathy (Berger disease) and Henoch-Schönlein purpura, systemic IgA vasculitis

Classically: gross hematuria with respiratory tract infection; can present anywhere in nephritic spectrum; Henoch-Schönlein purpura with vasculitic rash and gastrointestinal hemorrhage

Abnormal IgA glycosylation in both primary (familial predisposition) and secondary disease (associated with cirrhosis, HIV, celiac disease)Henoch-Schönlein purpura in children after an inciting infection

No serologic tests helpful; complement levels are normal

Pauci-immune (granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis [formerly Churg-Strauss], polyarteritis, idiopathic crescentic glomerulonephritis)

Classically as crescentic or RPGN, but can present anywhere in nephritic spectrum; may have respiratory tract/sinus symptoms in granulomatosis with polyangiitis

ANCAs: MPO or PR3 titers high; complement levels normal

Anti-GBM glomerulonephritis; Goodpasture syndrome

Classically as crescentic or RPGN, but can present anywhere in nephritic spectrum; with pulmonary hemorrhage in Goodpasture syndrome

May develop as a result of respiratory irritant exposure (chemicals or tobacco use)

Anti-GBM antibody titers high; complement levels normal

Cryoglobulin-associated glomerulonephritis

Often acute nephritic syndrome; often with systemic vasculitis including rash and arthritis

Most commonly associated with chronic hepatitis C; may occur with other chronic infections or some connective tissue diseases

Cryoglobulins positive; rheumatoid factor may be elevated; complement levels low

MPGN Classically presents with acute nephritic syndrome, but can see nephrotic syndrome features in addition

Most patients are < 30 years oldType I/immune complex most commonType II (dense deposit disease) and C3 glomerulonephritis

Low complement levels, may have findings of underlying infection or paraproteinemia

Hepatitis C infection Anywhere in nephritic spectrum Can cause MPGN pattern of injury or cryoglobulinemic glomerulonephritis; membranous nephropathy pattern of injury uncommon

Low complement levels; positive hepatitis C serology; rheumatoid factor may be elevated

Systemic lupus erythematosus Anywhere in nephritic spectrum, depending on pattern/severity of injury

Treatment depends on clinical course and International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification on biopsy

High ANA and anti-double-stranded DNA titers; low complement levels

Classification and findings in glomerulonephritis: nephritic spectrum presentations

Disease Typical Presentation Association/Notes

Minimal change disease (nil disease; lipoid nephrosis) Child with sudden onset of full nephrotic syndrome Children: associated with allergy or viral infectionAdults: associated with Hodgkin disease, NSAIDs

Membranous nephropathy Anywhere in nephrotic spectrum, but nephrotic syndrome not uncommon; particular predisposition to hypercoagulable state

Primary (idiopathic) may be associated with antibodies to PLA2RSecondary may be associated with non-Hodgkin lymphoma, carcinoma (gastrointestinal, renal, bronchogenic, thyroid), gold therapy, penicillamine, SLE, chronic hepatitis B or C infection

Focal and segmental glomerulosclerosis Anywhere in nephrotic spectrum; children with congenital disease have nephrotic syndrome

Children: congenital disease with podocyte gene mutation, or in spectrum of disease with minimal change diseaseAdults: associated with heroin abuse, HIV infection, reflux nephropathy, obesity, pamidronate, podocyte protein mutations, APOL1 mutations

Amyloidosis Anywhere in nephrotic spectrum AL: plasma cell dyscrasia with Ig light chain overproduction and deposition; check SPEP and UPEPAA: serum amyloid protein A overproduction and deposition in response to chronic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease, chronic infection)

Diabetic nephropathy High GFR (hyperfiltration) → microalbuminuria → frank proteinuria → decline in GFR

Diabetes diagnosis precedes diagnosis of nephropathy by years

HIV-associated nephropathy Heavy proteinuria, often nephrotic syndrome, progresses to ESRD relatively quickly

Usually seen in antiviral treatment-naïve patients (rare in antiretroviral therapy era), predilection for those of African descent (APOL1 mutations)

Membranoproliferative glomerulonephropathy Can present with nephrotic syndrome, but usually with nephritic features as well (glomerular hematuria)

Classification and findings in glomerulonephritis: nephrotic spectrum presentations

Cortex

Medulla

Proximal convoluted tubule Distal convoluted tubule

Cortical collecting duct

Loop of Henle Medullary collecting duct

X XX

High excretion of glucose, HCO3

-

phosphate, urate, amino acid…. NaCl wasting

Secondary K+ wasting Mg+2 wasting Low Ca+2 excretion Uosm max intact….

NaCl wastingLow K+ excretionUosm max intact

NaCl

Na+, Cl-, Ca+2 and Mg+2 wastingSecondary K+ wasting, Low Uosm max.

Ca+2

Mg+2

Defect

Conc

K+

Na+ and Cl- wasting, butno K+, Ca+2, or Mg+2 wasting

NaCl

HCO3-, Glucose,

Amino acids, phosphateNaClCa+2

Na+

K+

NaCl

Na+

XX

Organ System Symptoms Signs

General Fatigue, weakness Sallow-appearing, chronically ill

Skin Pruritus, easy bruisability Pallor, ecchymoses, excoriations, edema, xerosis

ENT Metallic taste in mouth, epistaxis Urinous breath

Eye Pale conjunctiva

Pulmonary Shortness of breath Rales, pleural effusion

Cardiovascular Dyspnea on exertion, retrosternal pain on inspiration (pericarditis)

Hypertension, cardiomegaly, friction rub

Gastrointestinal Anorexia, nausea, vomiting, hiccups

Genitourinary Nocturia, erectile dysfunction Isosthenuria

Neuromuscular Restless legs, numbness and cramps in legs

Neurologic Generalized irritability and inability to concentrate, decreased libido

Stupor, asterixis, myoclonus, peripheral neuropathy

Symptoms and signs of uremia

Stage Description GFR (mL/min/1.73 m2) Action

1 Kidney damage with normal or ↑↑ GFR ≥ 90 Diagnosis and treatment of underlying etiology if possible. Treatment of comorbid conditions. Estimate progression, work to slow progression. Cardiovascular disease risk reduction.

2 Kidney damage with mildly ↓ GFR 60–89

3a Mildly-moderately ↓ GFR 45–59 As above, and evaluating and treating complications.

3b Moderately-severely ↓ GFR 30–44

4 Severely ↓ GFR 15–29 Preparation for end-stage renal disease.

5 End-stage renal disease < 15 (or dialysis) Dialysis, transplant, or palliative care.

Stages of chronic kidney disease: a clinical action plan

Symptoms

Fatigue

Anorexia, Weight Loss

Headache

Flank pain

Arthralgias

Myalgias

Signs

Fever

Skin rash

Costovertebral Angle tenderness

Laboratory Findings

Blood studies: Renal Failure, Anemia, Eosinophilia

Urine studies: Sterile Pyuria, Proteinuria, Eosinophiluria, White Blood Cell Casts, Micro/Macroscopic Hematuria (rare)

Clinical Presentation of tubulointerstitial nephritis (TIN)

Drug-Related

Antimicrobials

NSAID's

Other

Infectious

Viral:

Cytomegalovirus, Hepatitis, HIV, Epstein - Barr virus, Hantavirus, Polyomavirus

Bacterial:

Salmonella, Streptococcus, Yersinia, Brucella, Leptospirosis

Fungal:

Histoplasmosis

Parasitic:

Leishmania, Toxoplasma

Localized TIN with acute pyelonephritis

Immune-Mediated

Sarcoidosis

Systemic Lupus Erythematosus

Sjögren's Disease

Inflammatory Bowel Disease

Idiopathic

TINU

Granulomatous TIN

Medications

Sarcoidosis

Tuberculosis

Bacterial/Fungal infections

TINU

Granulomatosis with polyangiitis

Etiology of TIN

Renal Histopathology in tubulointerstitial nephritis (TIN)A. TIN with

predominantly lymphocytic infiltrate associated with tubular damage and

tubulitis (arrow). Periodic acid Schiff stain, original magnification ×400. B. Acute drug-induced tubular injury, in this case secondary to cidofovir.

There is interstitial infiltrate (*), edema (#) and marked tubular regenerative

changes (arrows). Glomeruli show little change. Hematoxylin and eosin stain,

original magnification × 200. C.Granulomatous tubulointerstitial nephritis

(arrow), in this case likely secondary to lamotrigine. Hematoxylin and eosin

stain, original magnification × 200.

Renal infarct

Symptoms of renal failure and sometimes nausea, vomiting, flank pain, gross hematuria, decreased urine output, or systemic manifestations of venous thromboembolism may occur

Renal vein thrombosis