• manifestation of disease depends on site of tubule affected

1.proximal tubule (e.g. multiple myeloma, heavy metals)

Fanconi syndrome: decreased reabsorption in proximal tubule causing glycosuria,

aminoaciduria, phosphaturia, and hyperuricosuria

proximal RTA (decreased bicarbonate absorption):Type II RTA

2. distal tubule (e.g. amyloidosis, obstruction)

distal RTA (decreased hydrogen secretion, usually hypokalemic):Type 1 RTA

Na ' - wastingnephropathy

± hyperkalemia leading to Type IV RT A (where reduced renal bicarbonate production is

caused by hyperkalemia)

r t

L J

Presentation of Nephrotic Syndrome

HELP +

Hypoalbuminemia

Edema

Lipid abnormalities

Proteinuria

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NP28 Nephrology Toronto Notes 2023

3.collecting duct (e.g.sickle cell anemia, analgesics, primary ciliary dyskinesia)

urinary concentrating defect leading to mild nephrogenic D1

polyuria

1. ACUTE TUBULOINTERSTITIAL NEPHRITIS

Definition

• rapid (d to wk) decline in renal function

• 10-20% of all AK1

Etiology

• hypersensitivity

1. antibiotics:p-lactams,sulfonamides, rifampin, quinolones, cephalosporins, fluoroquinolones

2. other: NSAIDs, allopurinol, furosemide, thiazides, triamterene, PPls, acyclovir, phenytoin,

cimetidine

• infections

bacterial pyelonephritis, Streptococcus,brucellosis, Legionella,CM V, LBV, toxoplasmosis,

leptospirosis, HIV, Mycoplasma

• immune

• SLIi, acute allograft rejection, Sjogren'

s syndrome,sarcoidosis, mixed essential cryoglobulinemia

• idiopathic (renal-ocular syndrome - acute TIN plus uveitis)

Pathophysiology

• acute inflammatory cell infiltrates into renal interstitium

Clinical Features

• AKI

• if hypersensitivity reaction (common with antibiotics): may see fever, eosinophilia,skin rash,

arthralgia,scrum sickness-like syndrome (particularly rifampin)

• if pyelonephritis: Hank pain and costovertebral angle tenderness

• if drug reaction, AKI usually occurs 7-10 d alter exposure

• other signs and symptoms based on underlying etiology

• HTN and edema are uncommon

Findings

• urine

mild, non-nephrotic range proteinuria and microscopic hematuria

sterile pyuria, WBC casts

eosinophils if AIN

• blood work

increased Cr and urea

eosinophilia if drug reaction (high negative predictive value, common in (1-lactam reactions)

normal AG metabolic acidosis(RTA)

hypophosphatemia, hypo- OR hyperkalemia, hyponatremia

• gallium scan often shows intense signal due to inflammatory infiltrate

• renal biopsy definitive -shows interstitial infiltrates and edema on biopsy

Treatment

• treat underlying cause (e.g.stop offending medications,treat infection with antibiotics if present i.e.

pyelonephritis)

• corticosteroids(maybe indicated in allergic or immune disease)

Prognosis

• recovery within 2 wk if underlying insult can be eliminated

• the longer the patient is in renal failure, the less likely they will have a full renal recovery

2. CHRONIC TUBULOINTERSTITIAL NEPHRITIS

Definition

• characterized by slowly progressive renal failure, moderate proteinuria,and signs of abnormal tubule

function

Etiology

• persistence or progression of acute TIN

may also involve concurrent glomerular manifestations

• urinary tract obstruction:most important cause of chronic TIN (tumours,stones, bladder outlet

obstruction, vesicoureteral reflux)

• chronic pyelonephritis due to vesicoureteral reflux or UT1 with obstruction

• nephrotoxins

exogenous

analgesics: NSAIDs (common), acetaminophen

cisplatin, lithium, cyclosporine, tacrolimus

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XP29 Nephrology Toronto Notes 2023

heavy metals (lead, cadmium, copper, lithium, mercury, arsenic)

Chinese herbs (aristolochic acid)

endogenous

hypercalcemia, hypokalemia, oxalate, uric acid

•vascular disease: ischemic nephrosclerosis, atheroembolic disease

•malignancies:multiple myeloma,lymphoma

•granulomatous:TB,sarcoidosis, granulomatosis with polyangiitis

•immune:SLE, Sjogren’s, cryoglobulinemia, anti-GBM disease, amyloidosis, renal graft rejection,

vasculitis

• hereditary: cystic diseases of the kidney, sickle cell disease

•others: radiation, Balkan (endemic) nephropathy

Pathophysiology

•fibrosis of interstitium with atrophy of tubules, mononuclear cell inflammation

Signs and Symptoms

•dependent on underlying etiology

Findings

•non-AG metabolic acidosis

•hyperkalemia (out of proportion to degree of renal insufficiency)

•polyuria, nocturia

• partial or complete l

'

anconi’s syndrome

• progressive renal failure with azotemia and uremia

•urine: mild proteinuria, few RBCs and WBCs, no BBC casts

•U/S: shrunken kidneys with irregular contours (differentiates acute from chronic etiology)

Treatment

• stop offending agent or treat underlying disease

• supportive measures: correct metabolic disorders ((.

'

a

2

'

, H()i

l

) and anemia

3. ACUTE TUBULAR NECROSIS

Definition

•abrupt and sustained decline in (il-

'R within minutes to days after ischemic/nephrotoxic insult

•(il'R reduced (this serves the purpose of avoiding life-threatening urinary loss of fluid and electrolytes

from non-functioning tubules)

tllKtivcncss of Pinentioo Strategies for

Contrast-Induced Hepfiropatby: A Systematic

Review and Meta -Analysis

Arm Intern Med 20K:164f6|:406- 416

Purpose ro evaluate the comparative eftectiveness

of interventions to reduce contrast-induced

nephropathy n adults receiving contrast media.

Methods Heta -a-natysisofRCIsHacety tysteme.

sodium bicarbonate,statins, or ascorbic ltd that

used IV or intra-arterial contrast media.

Results: tow dose A acetyicjsteme

-IY saline

«. l*

saline 1#» 0.15.9S% C10.630.SS)

M -acetylcysteine

-IV saline is IV saline (RR 0.69.

95% Cl 0.58 0.84).Stall ns

-M -acetytcysteiae

-IV

sa me is. N acetytcysteine

-IV saline (ItIt 0.52.95% Cl

0.29-0.93).Clinically Important. Out not statistcally

significant, reductions were observed m sodium

bicarbonate is.IV salme.stabns

-IV saline is.N

saline, and ascorbic acid « IV saline.

Conclusions:Greatest red action in contrast-induced

nephropathy wasseen with H-acetylcystwne pusIV

saline andstatins plus N -acetylcysteme plus IV saline.

Etiology

( Acuto Tubular Necrosis"

)

Toxins Ischemia

£ 1 r

Decreased Circulating Volume

• Hemorrhage including post-surgical

• Skin losses

* Gllosses

* Renal losses

Exogenous

• Antibiotics

-Aminoglycosides

- Cephalosporins

-AmphotericinB

• Antiviral (cidofovir)

•Antineoplastics

-Cisplatin

-Methotrexate

• Contrast media

• Heavy metals

• Ollier

-Huorinated anesthetic

-Ethylene glycol

Endogenous

• Endotoxins (bacterial)

• Myoglobin

• Hemoglobin

• Tumour lysis syndrome

• Multiple myeloma

Decreased Effective Circulating Volume

• Heart failure

• Liver failure

• Sepsis

• Anaphylaxis

Vessel Occlusion

• Large or small renal artery involvement

Figure 17. Etiology of ATN

Clinical Features

• typically presents as an abrupt rise in urea and Cr after a hypotensive episode,sepsis, rhabdomyolysis,

or administration of nephrotoxic drug

• pre-renal AKI can eventually progress to ATN

consists of three phases:

oliguric: decreased urinary output from renal damage, azotemia, and uremia;lasts 10-14 d

diuretic: urinary’output >500 rnL/day (result of retained water,salt, and solutes during

oliguric phase) and tubular cell damage

recovery:tubular function recovers

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NP30 Nephrology Toronto Notes 2023

•physical exam may show signs of true or effective ECE volume depletion

•most common cause of non-prerenal AK1in hospitalized patients

•urine: high l-

'

ENa (>2%), pigmented-granular casts

Risk Factors

•pre-existing CKD, pre-existing cardiovascular disease, ECE volume depletion, multiple renal insults

Complications

•hyperkalemia:can occur rapidly and cause serious arrhythmias

•metabolic acidosis, decreased Ca increased P04 J “

, hypoalbuminemia

Investigations

•blood work:CBC,electrolytes,Cr, urea,Cat+, PO4 J-, blood gasses

•urine: R&M, electrolytes, osmolality, microscopic urinalysissearching for heme granular/muddy

brown casts

•ECU (monitor for arrhythmias due to hyperkalemia)

•abdominal U/S

•rule out other causes of prerenalfpostrenal azotemia and intrinsic AK1 (GN, AIN, vasculitis)

• IV fluid challenge will not increase urine output or normalize serum creatinine in ATN, helps to

differentiate ATN from pre-renal AK1

• if diagnosis is uncertain, biopsy

Treatment

•largely supportive once underlying problem is corrected

•consideration for early dialysis in scvere/rapidly progressing casesto prevent uremic syndrome (the

STARRT-AK1 study addressing this is ongoing)

Prevention

•correct fluid balance before surgical procedures

•for patients with chronic renal disease requiring radiographic contrast:

• isotonic saline

avoid giving diuretics, NSAIDS, ACE1, cyclosporine on morning of procedure if possible

•use renal-adjusted doses of nephrotoxic drugs in patients with renal insufficiency

•use low dose non-ionic, iso- or low-osmolal contrast agents

Vascular Diseases of the Kidney

LARGE VESSEL DISEASE

Table 13.Summary of Vascular Diseases

Large Vessel Disease Medium Vessel Disease Small Vessel Disease

Acute renal artery occlusion (infarct)

Renal artery stenosis(ischemia)

Renal vein thrombosis

Kawasaki disease

Polyarteritis nodosa

ANCAassociated vasculitis

Hypertensive nephrosclerosis

Atherocmbolic renal disease

thrombotic microangiopathy

Scleroderma

Calcineurin inhibitor nephropathy

HUS

ANCA- associated vasculitis

1. RENAL INFARCTION (ACUTE RENAL ARTERY OCCLUSION)

• important, potentially reversible cause of renal failure

Etiology

• abdominal trauma,surgery, embolism, vasculitis, extrarenal compression, hypercoagulable state,

aortic dissection

• kidney transplant recipients more vulnerable

Signs and Symptoms (depend on presence of collateral circulation)

• fever, N/V, Hank pain

• leukocytosis, elevated AST, ALP

• marked elevated LDH (LDH >4x upper limit of normal with minimal elevations in AST/ALT strongly

suggestive)

• acute onset HT'

N (activation of RAAS) orsudden worsening of long-standing HTN

• renal dysfunction, e.g. elevated Cr (if bilateral, orsolitary functioning kidney)

Investigations

• renal arteriography (more reliable but risk of atheroembolic renal disease)

• contrast

-enhanced CT or MR angiography, duplex Dopplerstudies (operator dependent)

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Treatment

• prompt localization of occlusion and restoration of blood flow

• anticoagulation, thrombolysis, percutaneous angioplasty or clot extraction,surgical thrombectomy

• medical therapy in the long-term to reduce risk (e.g. antihypertensives)

2. ISCHEMIC RENAL DISEASE (RENAL ARTERY STENOSIS)

• chronic renal impairmentsecondary to hemodynamically significant renal artery stenosis or

microvascular disease

• significant cause of ESRD:15% in patients >50 yr (higher prevalence if significant vascular disease)

• usually associated with large vessel disease elsewhere

• causes of renal artery stenosis

atherosclerotic plaques (90%): proximal 1/3 renal artery, usually males >55 yr,smokers

fibromuscular dysplasia (1096):distal 2/3 renal artery or segmental branches, usually young

females (typical onset <30 yr)

• when there is decreased RBF, GFR is dependent on angiotensin 11-induced efferent arteriolar

constriction which raisesthe FF (GFR/RBF)

• most common cause of secondary HTN (“renovascular HTN"), 1-2% of all hypertensive patients

etiology

t decreased renal perfusion of one or both kidneys leads to increased renin release and

subsequent angiotensin production

increased angiotensin raises blood pressure in two ways

1. causes generalized arteriolar constriction

2. release of aldosterone increases Na +and water retention

elevated blood pressure can in turn lead to further damage of kidneys and worsening HTN

Treatment of Hypertension in Association with

Renovascular Disease

Can J Cardiol 2117:33|5|:55?-$?6

Guidelines:

t. Recommend medical management as renal

angioplasty and stenting oilers no benefit over

optimal medical tlrerapyalone

2. In patients with uncontrolled HTN resistant to

maximally tolerated pharmacotherapy, progressive

renal function lossand acnte pulmonary edema,

renal artery angioplasty andstenting (or

atherosclerotic hemodynamically significant

stenosis could be considered

3. Patients with confirmed renalfibromuscular

dysplasia should be tefened to HTN speclallstand

considered for revasculariaation

Risk Factors

• agc* >50 yr

• smoking

• other atherosclerotic disease (dyslipidemia, DM, diffuse atherosclerosis)

Signs and Symptoms

• severe/refractory HTN and/or hypertensive crises, with negative family history of HTN

• asymmetric renal size

• epigastric or flank bruits

• spontaneous hypokalemia (renin activation in under-perfused kidney)

• increasingCr with ACE1/ARB

• flash pulmonary edema with normal LV function

Investigations

• must establish presence of renal artery stenosis and prove it is responsible for renal dysfunction

• duplex Doppler VIS (kidney size, blood flow):good screening test (operator dependent)

• digital subtraction angiography (risk of contrast nephropathy)

• CT or MR angiography (effective noninvasive tests to establish presence of stenosis,for MR avoid

gadolinium contrast if eGFR <30 mL/min because of risk of systemic dermal fibrosis)

• ACE1 renography (e.g.captopril renalscan)

• renal arteriography (gold standard, but risk of contrast nephropathy)

Stenting and Nodical Therapy for Athcroiclcrotk

Renal ArteryStenosis

NfJM 2014:370:13-22

Study:Multicentre.uuDlmded RCI.median follow-up

of 43 mo.

Patients:94? patients with atherosclerotic renalartery stenosis who also have significa ntsystolic

HTN or CKO.

Intervention: 041 patients with atherosclerotic

renal-artery stenosa who also havesigmficant

systolic HIN or CKO.

Intervention:Percutaneousrevascularization

(stenting) with medical therapy (statins, ARB. calcium

channel blotters,HCTZ.and 8P control) vs.medical

therapy alone.

Outcomes:Occurrence of adverse CV or renal event

(coon postte of death from CV or renalcause. Ml.

stroke, hospitalization foi CNF, progressive renal

insufficiency, or need for renal replacement therapy)

and all-cause mortality.

Outcomes:Occurrence of adverse CV or lenalevent

(composite of death from CVor renal cause, Ml,

stroke, hospitalization for CKF, progressive renal

insufficiency,or need for renal replacement therapy)

and all-cause mortality.

Results:Ho sigmficantdiNerence in primary

composite endpoint between participants who

received stenting or those on medical therapy alone.

No significant differences between the treatment

groups in the rates of the tdividual componentsof

the primary endpointor in all-cause mortality..

Conclusion:Renal arterystenting did not confer a

significant benefit with respect tothe prevention

of cl inical events when added tocomprehensive,

multifactorial medical therapy in people with

atherosclerotic renal artery stenosis and HTN or CKO.

Treatment

• treatment of renal artery stenosis is performed for select cases of blood pressure control, treatment of

heart failure, pulmonary edema, and prevention of nephropathy

• medical therapy includes potential use of ACE1,statins, and platelet inhibitors

• revascularization using stenting is performed to treat or prevent development of ischemic

nephropathy,although there is debate surrounding its efficacy

• surgical bypass or reconstruction is an option but benefit over angioplasty is debated

3. RENAL VEIN THROMBOSIS

Etiology

• endothelial damage:blunt trauma, tumour infiltration (e.g. RGC), vasculitis,renal transplant, and

acute rejection

• stasis:severe volume loss (i.e. G1 fluid loss, hemorrhage, dehydration), renal vein compression

• hypercoagulability: nephrotic syndrome,sepsis,oral contraceptives, disseminated malignancy,

intrinsic hypercoagulability,sickle cell disease

• hypercoagulable states(e.g. nephrotic syndrome, especially membranous), ECF volume depletion,

extrinsic compression of renal vein,significant trauma, malignancy (e.g. RGC),sickle cell disease

• clinical features determined by rapidity of occlusion and formation of collateral circulation

n

j

Signs and Symptoms +

• acute:N/V,flank pain,hematuria,elevated plasma LDH, ± rise in Cr,sudden rise in proteinuria

• chronic: PE (typical first presenting symptom), increasing proteinuria, and/or tubule dysfunction

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NP32 Nephrology Toronto Notes 2023

Investigations

• renal venography (gold standard),CT or MR angiography, duplex Doppler U/S

Treatment

• anticoagulation therapy to aid in recanalisation, improve renal function, and reduce risk of

thromboembolism. Initial treatment using IV heparin, followed by warfarin (target INK 2.5) within

3-10 d continued for minimum I yr

• certain cases are suitable for thrombectomy or thrombolysis(local or systemic).Commonly used

agents include streptokinase, urokinase, and tissue plasminogen activators

MEDIUM VESSEL DISEASE

1. KAWASAKI DISEASE

• see Paediatrics.P98

2. POLYARTERITIS NODOSA

• see Rheumatology. RH21

• kidneys most commonly involved organ

• heterogenous impact on renal function

• pathologically can cause glomerular ischemia which manifests as mild proteinuria and hypertension

SMALL VESSEL DISEASE

1. HYPERTENSIVE NEPHROSCLEROSIS

• see Hypertension, NP37

2. ATHEROEMBOLIC RENAL DISEASE

• progressive renal insufficiency due to embolic obstruction ofsmall- and medium-sized renal vessels

by atheromatous emboli

• spontaneous or after renal artery manipulation (surgery, angiography, percutaneous angioplasty)

• anticoagulants and thrombolytics interfere with ulcerated plaque healing and can worsen disease

• investigations

• eosinophilia, eosinophiluria, and hypocomplementemia

renal biopsy:needle-shaped cholesterol clefts (due to tissue-processing artifacts) with

surrounding tissue reaction in small-/medium-sized vessels

Reduced Exposure to Calcineurin Inhibitors in

Renal Transplantation ftllTESymphony Trial)

tlEJM 2007:2S7:2S62 2S7S

Study Mi ticentre. RCIwilh 12 mo lotlow-up.

Patents:1645 patientsscheduled to receive a single

organ kidney transplant

Intervention:Mycophenoiatemofetil,

corticosteroids, and either:1)standard dose

cytlotpoiine: 2) lowdose cyclosporine with

daclnumab induction; 3)low dose tacrolimus with

daclitumab induction: 4|low dose sirolimus with

dacliumab induction.

Primary Outcome:Estimated Cockcroft-Gaidt 6ER12

mo after transplantation.

Results: The tacrolimusarm showed significantly

higher eCFR at 12 mo compared to all other arms

(6S.4 mllmln rs. 57.1,59.4.St.Jlor arms1, 2, 4

respectively,PsO.OOl).the catrohmusarm also

showed decreased ratesof acute rejection at 6 mo

and12 mo vs.all arms(MLOOI).improved allograft

survival against standard dose cyclosporine and

sirolimus. and decreased treatment failure against

all ©titer arms. There was no difference in overall

patientsunrlval between groups. Sirolimus had the

highest incidence oflymphoceles, delayed wound

healing,and serious adverse events; tacrolimus

bad significantly higher rate of new-unsetIW;and

cyclosporine regimes had the lowest incidence of

diarrhea hut highest opportunistic infection rates.

Conclusion:Immunosuppression regiments uimg

low dose tacrolimus and dacliumab induction

decrease nephrotoxicity while maintaining

therapeutic immunosuppression in renal transplant

patients

treatment

no effective treatment; avoid angiographic and surgical procedures in patients with diffuse

atherosclerosis,medical therapy for concomitant cardiovascular disease

• prognosis:poor overall, at least one third will develop ESRD

3. THROMBOTIC MICROANGIOPATHY

• see Hematology. H23

• etiologies include the spectrum of TTP-HUS, DIC,severe preeclampsia, drug-induced, complement

mediated, metabolism-mediated, and coagulation-mediated

• the enzyme ADAMTS13 is reduced in T I P,and ADAMTS13 autoantibodies are useful for diagnosing

TTP

• events leading to HUS often begin with the ingestion of Shiga toxin-producing E. coli

• renal involvement more common in HUS than TTP

• renal involvement characterized by fibrin thrombi in glomerular capillary loops ± arterioles

• treatment

depends on cause

• supportive therapy

w TTP- HUS: plasma exchange, corticosteroids (splenectomy and rituximab if refractory)

• avoid platelet transfusions and ASA

4. CALCINEURIN INHIBITOR NEPHROPATHY

• secondary to the use of cyclosporine and tacrolimus

• causes both acute reversible and chronic, largely irreversible nephrotoxicity

• major cause of kidney failure in other solid organ transplants(e.g. heart)

• acute: due to afferent and efferent glomerular capillary constriction leading to decreased CiTK (tubular

vacuolization)

prerenal azotemia

• treatment: calcium channel blockers or prostaglandin analogs, reduce dose of cyclosporine or

switch to another immunosuppressive drug

• chronic:result of obliterative arteriolopathy causing interstitial nephritis and CKD (striped fibrosis),

less frequent now due to lower doses of calcineurin inhibitors

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Analgesic Nephropathies

DM isone of the causes of ESRD that

does notresultin small kidneys at

presentation of ESRD;the others are

amyloidosis. HIV nephropathy PKD, and

multiple myeloma

1. Vasomotor AKI

clinically: develop prerenal azotemia days after NSA1D initiations

normally prostaglandins vasodilate afferent renal arteriole to maintain blood flow

NSAlDs act by inhibiting cyclooxygenase activity, thereby preventing prostaglandin synthesis and

causing renal ischemia

more common in elderly, underlying renal disease, hypovolemia (diuretics, CH1

;

, cirrhosis, nephrotic

syndrome)

treatment:discontinue NSAID, dialysis rarely needed Abnormal Urine ACR Values from 2018

Diabetes Canada CPG

2. Acute Interstitial Nephritis i2.0 mg/mmol in males and females

caused by fenoprofen (60%), ibuprofen, naproxen

may be associated with minimal change glomerulopathy and nephrotic range proteinuria

resolves eventually with discontinuation of NSAID, may require interval dialysis

short-term high dose steroids(1 mg/kg/d of prednisone) may hasten recovery ACEI can cause hyperkalemia;therefore,

be sure to watch serum K*. especially if

3. Chronic Interstitial Nephritis patient has DM and renal insufficiency

due to excessive consumption of antipyretics(phenacetin or acetaminophen) in combination with

NSAlDs

seen in patients who also have emotionalstress, psychiatric symptoms,and G1 disturbance

papillary necrosis occurs

gross hematuria, flank pain, declining renal function

• calyceal filling defect seen with 1VP - “ring sign”

increased risk of transitional cell carcinoma of renal pelvis

good prognosis if discontinue analgesics

Os (Urine Protein)

Normal

I

4. Acute Tubular Necrosis

can be caused by acetaminophen

incidence of renal dysfunction is related to the severity of acetaminophen ingestion

vascular endothelial damage can also occur

both direct toxicity and ischemia contribute to the tubular damage

renal function spontaneously returns to baseline within 1-4 wk

dialysis may be required during the acute episode of ingestion

5. Other Effects of NSAlDs

sodium retention (2°to reduced GTR)

hyperkalemia, H'

l

'

N (2°to hyporeninemic hypoaldosteronism)

excess water retention (2

s

to loss of antagonistic effect of prostaglandins on ADH )

0

Time

Figure18. GFR and urine protein

over time in DM

ProteinRestriction for Diabetic RenalDisease

Cochrane DB Syst Rev 2007;4:CD002181

Purpose: To review the eNects of dietary

protein restriction on the progression of diabetic

nephropathy.

Study Selection:RCIsand before and afterstudiesol

the effects of restricted protein diet on renal fnnciioo

in subjects with DM.12 studies were reviewed.

Results:Ihe risk of ESRD or death was lower in

patients on low-protein diet.In patients with type

1 DM no effect on WR was noted in the low- protein

diet group.

Systemic Disease with Renal Manifestation

Diabetes

• diabetic nephropathy is a slow, progressive increase in albuminuria,followed by a decrease in eGl-

'

R

<60 later in disease course

• key risk factors include:

• long duration of diabetes

• non-optimal glycemic control, blood pressure,and plasma lipid control

obesity

• cigarette smoking

• most common cause of end-stage renal failure in North America

• 50% of patients with diabetes will develop nephropathy

• greater burden in Indigenous communities

in Indigenous youth diagnosed with diabetes before age 20, risk of developing ESRD was 2.59

times higher than non-Indigenous people with diabetes

55.1% of Indigenous individuals diagnosed with diabetes had chronic kidney disease

• at diagnosis up to 30% of patients with type 2 DM have albuminuria (75% microalbuminuria, 25%

overt nephropathy)

• microalbuminuria is a risk factor for progression to overt nephropathy and cardiovascular disease

• once macroalbuminuria is established, renal function declines,50% of patientsreach ESRD within

7-10 yr

• associated with HTN and diabetic retinopathy (especially type 1 DM) and /or neuropathy (especially

type 2 DM)

See landmark Nephrology hull table for more

information onOHIARGEI. whictr detailsItie eMkacy

of ACEI/ASB combination therapy on renal outcomes

kr patients with atherosoderotic vascular diseaseor

I2DM.- slightly t mesangial matrix

See landmark Nephrology Irialstable for more

information on CREDENCE which detailsthe effkacy

dcanagliflozin (SGLT2 inhibitor) on renal outcomes in

patients with T 2DM an diabetic nephropathy

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NP34 Nephrology Toronto Notes 2023

•indication of possible non-diabetic cause of renal disease in patients with DM

rising Cr with little/no proteinuria

lack of retinopathy or neuropathy (microvascular complications)

persistent hematuria (microscopic or macroscopic)

signs orsymptoms ofsystemic disease

inappropriate time course;rapidly risingCr,renal disease in a patient with short duration of DM

family history of non-diabetic renal disease (e.g.PKD, Alport’s)

DIABETIC RENAL COMPLICATIONS

1.Progressive Glomerulosclerosis

•classic diabeticglomerular lesion:Kimmelstiel-Wilson nodular glomerulosclerosis (15-20%)

•more common lesion is diffuse glomerulosclerosis with a uniform increase in mesangial matrix

Table 14. Stages of Diabetic Progressive Glomerulosclerosis

Stage 1 Stage 2 Stage 3 Stage 4

Detectable

raiaoalbaJBiauria (0-300

rag/24b)

«8 2.0-20 mg mmol ACR >20 mg/mmol.(>180 mg/d) GFR

(18-180rag'

d)

Hacroalbuminufia (>300 mgi'24 h) » proteinuria (>500

mg/24 h)

Clinical tGFR|120-1$0%)

- compensatory

hyperfiltration

Proteinuria (positive urine

dipstick)

Normal GFR

Pathological t slightly t mesangial tit mesangial matrix Sclerosed glomeruli

matrix

<20% glomerular filtration

surface area present

2. Accelerated Atherosclerosis

• common

• leads to decreased GFR

• may increase angiotensin 11 production resulting in increased BP

• increased risk of ATN secondary to contrast media

3. Autonomic Neuropathy

• causes atonic bladder, which leadsto functional obstruction and urinary'retention

• residual urine promotes infection

• obstructive nephropathy

4. Papillary Necrosis

• type 1 DM susceptible to ischemic necrosis of medullary papillae

• sloughed papillae may obstruct ureter

• can present as renal colic or with obstructive features ± hydronephrosis

Priorities in the Management of Patients with DM

1. vascular protection for all patients with DM

ACE1, antiplatelet therapy (as indicated)

BP control,glycemic control,lifestyle modification, lipid control

SGLT2 inhibition (i.e.canaglitlozin,dapaglitlozin,and empagliflozin) provides renoprotection

independent of glycemic effects

mineralocorticoid receptor antagonists(i.e.finerenone) provide renoprotection of top of RAAS

blockade

2.optimization of BP in patients who are hypertensive

treat according to H1N guidelines

3.renal protection for DM patients with nephropathy (even in absence of HTN)

- type 1 DM:ACHlorARB

type 2 DM:CrCl >60 mL/min:ACEI or ARB;CrCl <60 mL/min:ARB

2nd line agents: nondihydropyridine calcium channel blockers (diltiazem,verapamil)

combination of ACEI and ARB not recommended

4.smoking cessation

• check serum Cr and K+

levels within 1 wrk of initiating ACEI or ARBand at time of acute illness

• serum Cr can safely be alkwed to rise up to 30% with initiation of ACEI or ARB, usually stabilizes

after 2-4 wrk,monitorforsignificant worsening of renal function or hyperkalemia

• if >30% rise in serum Cr or hyperkalemia, discontinue medication and consider 2nd line agent

• consider holding ACEI,ARB,and/or diuretic w'ith acute illness and in women before pregnancy

• consider referral to nephrologist if ACR >60 mg/mmol,eGFR <30 mL/min, progressive loss of kidney

function, inability to achieve BP targets,or inability tostay on ACEI or ARB

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XP35 Nephrology Toronto Notes 2023

Screen annually when no transient causes of albuminuria or low eGFR are present,

and when acute kidney injury or non-diabetic kidney disease is notsuspected

Typo 1 diabetes: Annually in postpubcrtal individuals with duration of diabetesi5 yr

Typo 2 diabetes: At diagnosis and annually thereafter

^

Order random urine ACR and scrum creabnine for eGFR j

1

eGFR £60 mL/min OR ACR>.2 mgimmol?

I NO ; ; yES >

Random urine ACR >20 mg/mmol?

Orderserum creatinine for eGFR in 3mo AND

2 repeat random urine ACRs performed over next3mo

T

At 3 mo

oGFR 3» mL/min or 2 or3out of 3ACRs >2 mg/mmol?

H NO |

( YES

Chronic Kidney Disease Diagnosed

Figure 19. Clinical practice guidelines on chronic kidney disease in diabetes

Dlabutu

*

Canada ClinicalPtacUce Guideline

*

Expert Committee. Diabetes Canada 2018 ClinicalPractice Guideline

*

for the Prevention and

Management of Diabetes In Canada.Can J Diabetes 2018;42(Suppl1):S1-S325

Scleroderma

• see Rheumatology, RH14

• 50% of patients with scleroderma have renal involvement (mild proteinuria,high Cr, HTN)

• renal involvement usually occurs early in the course of illness

• histology: media thickened,"onion skin"

hypertrophy of small renal arteries, fibrinoid necrosis of

afferent arterioles and glomeruli

• 10-15% ofscleroderma patients have a “scleroderma renal crisis” (occurs in first few years of disease):

malignant HTN, ART, microangiopathy, volume overload, visual changes, HTN encephalopathy

• treatment:BP control with ACE1 slows progression of renal disease

Multiple Myeloma

• see Hematology, H 51

• malignant proliferation of plasma cells in the bone marrow with the production of immunoglobulins

• patients may present with severe bone disease and renal failure

• light chains are filtered at the glomerulus and appear as Bence-Jones proteins in the urine

(monoclonal light chains)

• kidney damage can occur by several mechanisms

hypercalcemia

light chain cast nephropathy or “myeloma kidney"

hyperuricemia

• infection

secondary amyloidosis

• monoclonal Ig deposition disease

diffuse tubular obstruction

• light chain cast nephropathy

large tubular casts in urine sediment (light chains t Tamm-Horsfall protein)

• proteinuria and renal insufficiency can progress rapidly to kidney failure

• monoclonal immunoglobulin deposition disease

deposits of monoclonal lg in kidney, liver, heart,and other organs

mostly light chains(85-90%)

causes nodular glomerulosclerosis (similar to diabetic nephropathy)

• lab features: increased BUN, increased Cr, urine protein immunoelectrophoresis positive for BenceJones protein (not detected on urine dipstick)

• poor candidatesfor kidney transplantation

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NP36 Nephrology Toronto Notes 2023

Malignancy

2016 CCS Guidelines lot the Management at

Dyslipidemia lor the Prevention of CVD in the

A dull- Chronic Kidney Disease

Can J Cardiology 2016;32:1263-82

Recommendations:

Ad-jits >50 yrwithCKD|GFR <60 miyo«tfl)3n |J

shoo'

d receive treatment with a statin or a stat'

d

ezetinibe combination.

Inrtiation ol lipid-lowering therapy is not

recommended for adolts with d-alysis-dependent

CKO however, f already receirng it at the time of

dialysis initiation, itshonld be continoed.

•Statin therapy should be used in adults with kidney

transplantation.

• cancer can have many different renal manifestations

• kidney transplantation cannot he performed if there is a malignancy. Nephrology considerationsfor

malignant presentations include:

solid tumours: mild proteinuria or membranous GN

lymphoma: minimal change GN (Hodgkin’s) or membranous GN (non-Hodgkin’s)

• renal cell carcinoma

tumour lysissyndrome: hyperuricemia, diffuse tubular obstruction, hyperkalemia,

hyperphosphatemia, hypocalcemia, lactic acidosis

chemotherapy (especially dsplatin): ATN or chronic TIN

• pelvic tumours/metastases: postrenal failure secondary to obstruction

2° amyloidosis

• radiotherapy ( radiation nephritis)

Chronic Kidney Disease

Definition

• progressive abnormalities of kidney function for >3 mo, with either

GIR <60 mL/min/1.73 m 2; or

’

markers of kidney damage, including:

hematuria, proteinuria, or anatomic abnormalities

Incidence ol Etiologies of CKD

DM 42.9%

HTN 26.4%

Glomerulonephritis

Other/Unknown

Interstitial nephritis/

Pyelonephritis

Cystic/Hcreditary.1Congenital 3.1%

Secondary GN,

'Vasculitis 2.4%

9.9%

7.7%

Clinical Features

• cardiovascular: HTN, CHE (volume overload, HTN, and anemia), pericarditis (uremia )

• Gl:N/V,anorexia

• neurologic:lethargy, confusion, neuropathy,seizures, asterixis, hyperreflexia, restless leg syndrome,

encephalopathy (uremia)

• hematologic: normocytic normochromic anemia ( reduced EPO), bleeding due to platelet dysfunction

(uremia)

• endocrine/metabolic: Ga POt * disturbances, hyperphosphatemia, hypocalcaemia,secondary

hyperparathyroidism, reduced renal production of 1,25-dihydroxy vitamin D, osteopenia/osteoporosis

• sexual/reproductive: hypothalamic pituitary disturbances, infertility

• pruritus: multifactorial etiology

4.0%

Management of Complications of CKD

NEPHRON

L ow-Nitrogen diet

Electrolytes: monitor K+

pH:metabolic acidosis

Table 15. Stages of CKD (KDIGO, 2013)

Persistent Albuminuria Categories

GFR A1 A2 A3 HTN

(mL/min/1.73 m2 ) <30 mg/g

<3 mg/mmol

30-300 mg/g

3-30 mg/mmol

>300 mg/g

>30 mg/mmol

RBCs: manage anemia with

erythropoietin

Osteodystrophy: give calcium between

meals (to increase Ca 2t

) and calcium

with meals (to bind and decrease POD)

Nephrotoxins:avoid nephrotoxic drugs

(ASA. gentamicin) and adjust doses of

rcnally excreted medications

GFR Categories

(mL/min/1.73 m'

j

G1 >90 1it CKD 1 2

G 2 60 89 lit CKO 1 2

G 3<t 45-59 1 2 3

G 3b 30 44 2 3 3

G4 15 29 3 3 4*

G5 <15 (kidney failure) 4< 4* 4»

Effects ol lowering IDt Cholesterol with

Simvastatin and Ezetimibe in Patients with

Chronic Kidney Disease

lancet 2011:377:2181-2192

Purpose:fo assessthe efficacy and safety ofSe

combination ofsimvastatin and ezetimibe in patients

with moderate to severe CKD.

Study:Randomized, double-blind trial with

9270 patients with CKD with no known history of

myocardial infarction or cotonaiy vascularization.

Patients were randomized tosmvastatxi 20 ng plus

ezebmibe 10 mg daily vs. matching placebo.

Primary Outcome: First major atherosclerotic

event (non-fatal myocardial infarction or coronary

death, nan-hemorrhagic stroke,or any arterial

revascularization procedure).

Results: Ilie simvastatin plus ezefnPe group

was associated with an average101cholesterol

difference of 0.85mmol/l during a median follow- up

ol 4.9 yr. There was a 17% proportional leduclnn in

major atherosclerotic evenb in the simvastatin plus

ezetimibe group compared to placebo.

Conclusions: Reducing LDlcholesterol with a

treatment regimen of siravastabn plus ezetimibe

safely reduced the incidence of major atherosclerotic

everts in patientswdh mode rate to severe CKD.

The numbersin the boxes are a reflection of lire risk of progression and are a guide to the frequency ol inonltoring/year

'

0

'

isadded to 65lor patients requiring dialysis

Classification is based on cause.GFR.and amount ot albuminuria

Rate ot progression and risk ot complications are determined by the cause of CKD

Management of Complications of CKD

Management of Chronic Kidney Disease

• diet

• preventing HTN and volume overload

low-protein diet with adequate caloric intake in order to limit endogenous protein catabolism.

Not recommended in children as protein is needed for growth. Literature is conflicted regarding

use of protein restriction in certain other populations

Na '

restriction (<2 g/d ) if HTN, CH!•

'

,or oliguria are present

K restriction (40-60 mmol/d), phosphate (1 g/d) and magnesium (avoid antacids; preventing

uremia and potentially delaying decline in GI R) intake

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• medical

adjust dosages of renally excreted medications

HTN:zVCEl (target 140/90 mmHg without DM and 130/80 mmHg with DM), loop diuretics when

GER <25 mL/min

dyslipidemia:statins (target LDL <2 mmol/L)

+

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NP37Nephrology Toronto Notes 21)23

calcium and phosphate disorders

consider vitamin D and calcitriol (1,25-dihydroxy-vitamin D) if hypocalcemic, but hold if

hyperphosphatemic (reduces PTH)

sevelamer (phosphate binder) if both hypercalcemic and hyperphosphatemic

cinacalcet for hyperparathyroidism (sensitizes parathyroid to Ca- T, decreasing PTH)

metabolic acidosis:sodium bicarbonate

• anemia: erythropoietin injections for Hb <90 g/L (9 g/dL) and target Hb between 90-115g/L (9-

10.5 g/dL). IV Iron administration often required for iron deficiency

• clotting abnormalities: DDAVP if patient has clinical bleeding or invasive procedures (acts to

reverse platelet dysfunction)

• dialysis (see Indications for Dialysis in Chronic Kidney Disease , N M I )

renal transplantation for end stage kidney disease

Prevention of Progression

•as above

•control of HTN, DM (HbAlc <7%), cardiovascular risk factors (e.g.smoking cessation, physical

activity, weight loss)

•avoid nephrotoxins such as NSAIDs, (X)XIBs, IV contrast in patients with etil'

R <60 mL/min/1.73 m -

•address reversible causes of AKI

Renin Angiotensin System Blockade and

Cardiovascular Outcomes in Patients with Chronic

Kidney Diseascand Proteinuria: A Meta-Analysis

A.nKeartJ 2008;155:791-805

Purpose: lo evaluate the role of RAS blockade in

^

proving uidiovasculai W outcomes In patients

with CKO.

Study Selection: RCI that analyied CV outcomes

m patents with CKD/protcinuiia treated with RAS

blockade (ACEHARB). RAS blockade- based therapy

was compaied ndh placebo andcontrol therapy

(J-hlocker.cakum-channel hlockers. and other

anphyperteasii'e -hased therapy) in the study.

Results:Twenty-five trials(n^45758) were included.

Compared to platehb, RAS blockade reduced the risk

ol heart laiLiem patients with diabetic nephropathy.

In patients with non -diabetic CXD. RAS blockade

decreased CV outcome compaied toconlrol therapy.

Conclusions: RAS blockade reduced CVouUomesia

diabetic nephiopalhy as well as non-diabetic CKO.

Hypertension

• see family Medicine. l

'M37

• HTN occurs in about 20% of population

• etiology classified as primary (“essential;” makes up 90% of cases) orsecondary

• primary HTN can cause kidney disease (hypertensive nephrosclerosis), which may in turn exacerbate

the HTN

• secondary HTN can he caused by renal parenchymal or renal vascular disease

Hypertensive Nephrosclerosis Elltdi of Intensive BP Control in CKD

J Am Soc Nephrol 2017:28|9|:2812 2823

Rjrpose To eva uale appropriate target for BP in

patiertswith CKD and HTN.

Methods:RCIsubgroup analyses of participants

- the Systolic Blood Pressure Intervention Trial

(SPRIMI).Part cipanls were randomly assigned to

ntensnre group (sBP <120 mmHgl or standard group

(sBP <HOmmHg).

Results: Ihe intensive group had a lower rate ol

a thus*

death (HR 0.72. 9'A Cl 0.63-1.05) and major

CVerentsIHR 0.81. 9511 Cl 0.63-1.05). Decreases m

eCFR were com parable between treatment groups

(HR 0.90.95% Cl 0.44 1.83). Treatment eHectsdid not

Offer between participants with and withoutCKD.

Conclusions:In patientswith CKD and HTH without

(tabetes.targetsBP of 120 mmHg vs.140 mmHg

red.ced rates of major CV events and all-cause death.

Table 16. Chronic vs. Malignant Nephrosclerosis

Chronic Nephrosclerosis Malignant Nephrosclerosis

Histology Slow vascular sclerosis with ischemic changes affecting

intralobular and afferent arterioles

Black race,underlying CKO.chronic hypertensive disease Acute elevation in BP|d8P *120 mmHg)

HIM encephalopathy

Proteinuria and hematuria (R6C casts)

lowet dBP to 100-110 mmHg within 6-24 h

More aggressive Irealmentcan cause ischemic event

Identify and treat underlying causeof HIII

Can progress lorenal failure despite patientadherence Lower survival ifrenal insufficiency develops

Fibrinoid necrosis of arterioles,disruption of vascular

endothelium

Clinical Picture

Urinalysis

Therapy

Mild proteinuria,normal urine sediment

Blood pressure control. (target «140/90) with frequent

follow-up

Prognosis

Renovascular Hypertension

• see Vascular Diseases of the Kidney, NKMI

Renal Parenchymal Hypertension

•HTN secondary to GN, AIN,diabetic nephropathy, or any other chronic renal disease

•mechanism of HTN not fully understood but may include:

excess RAAS activation due to inflammation and fibrosis in multiple small intra-renal vessels

production of unknown vasopressors, lack of production of unknown vasodilators, or lack of

clearance of endogenous vasopressor

• ineffective sodium excretion with fluid overload

Investigations

•as well as investigations for renovascular HTN, additional tests may include

24 h urinary estimations of CrQ and protein excretion

imaging (U/S, CT)

serology for collagen-vascular disease

renal biopsy (very rarely if at all)

r “k

i j

Treatment +

•most chronic renal disease is irreversible; however, treatment of HTN can slow the progression of

renal insufficiency

•control LG volume: Na 'restriction (2 g/d intake), diuretic, dialysis with end-stage disease

•AGil or ARB may provide added benefit (monitor K '

and Cr) if there issignificant proteinuria (>300 mg/d)

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NP38 Nephrology Toronto Notes 2023

Cystic Diseases of the Kidney

• characterized by epithelium-lined cavities filled with fluid or semisolid debris within the kidneys

• includes:simple cysts (present in 50% of population >50), medullary cystic kidney, medullary sponge

kidney, polycystic kidney disease (autosomal dominant and recessive), and acquired cystic kidney

disease (in chronic hemodialysis patients)

Hypercalcemia complicates many

cancers and can cause multiple kinds ol

renal disorders(renal vasoconstriction

with reduced GFR.salt-wasting with

volume depletion, risk ol calcium kidney

stones)

Adult Polycystic Kidney Disease

•autosomal dominant; at least 2 genes: PKDI (chr 16p) and PKD2 (chr 4q)

.PKDI (1:400), PKD2 (1:1000) accounts for about 10% of cases of renal failure

•patients generally heterozygous for mutant PKD gene but accumulate a series ofsecond ‘

somatic hits’

precipitating the condition

•PKD gene defect leads to abnormal proliferation and apoptosis of tubular epithelial cellsleading to

cyst growth

•most common extrarenal manifestations: multiple asymptomatic hepatic cysts (33%), mitral valve

prolapse (25%), intracranial arterial aneurysm (10%), diverticulosis,hernias (abdominal/inguinal)

•polycystic liver disease rarely causesliver failure, but may form the indication of liver transplant due

to space occupying impact which can lead to reduced oral intake and malnutrition

•less common extrarenal manifestations:cystsin pancreas,spleen,thyroid,ovary,seminal vesicles,

and aorta

Extrarenal Manifestations of PKD

• Hepatic cysts

. Mitral valve prolapse

• Cerebral aneurysms

. Diverticulosis

Totnpta Later-SCage AitKoaalDoaiuxt

Polycystic EtoeyDisease

IEJK 2017:377:1930-1842

PnposeToera Be eScacysdsa^

ty of

Be laupresasY2-receytixasBgoa-sttohaytes

la patiesS laer-stage aiiosmal teases!

xlycystic bdsey feease.

: : . : = :

aiticeatre.ptecEtio-coatraaed.tatie-titiMtrial,

lesalts:Q-argeseslsatedfflfme dasaiseaas

. •

'

. ; . :I : .

-2J1io-187)tv -3-61—-.1732 a fcBeplacate

grasp(9S% CL -4.08 to -3-W|

-

Coochniots To ,a:Sinotedaa dooer dectoe

Baa placetnEBeestisatidCFtner a1yrperiodSignS and Symptoms

•often asymptomatic; discovered incidentally on imaging or by screening those with THx

•acute abdominal flank pain/dull lumbar back pain (source:infection of renal cysts, hemorrhaging into

cysts,kidney stones)

•hematuria (frequently initialsign is microscopic hematuria, otherwise gross hematuria)

•nocturia (urinary concentrating defect)

•extrarenal presentation (e.g. ruptured berry aneurysm, diverticulitis,mitral valve prolapse,aortic

regurgitation, tricuspid valve prolapse)

•HTN (increased renin due to focal compression of intrarenal arteries by cysts) (60-75%)

•± palpable kidneys

Common Complications

•urinary tract and cyst infections, HTN, chronic renal failure, nephrolithiasis (5-15%),flank and

chronic back pain

Clinical Course

•polycystic changes are always bilateral and can present at any age

•clinical manifestations rare before age 20-25

•kidneys are normal at birth but may enlarge to lOx normalsize

•variable progression to renal functional impairment (ESRD in up to 50% by age 60)

Investigations

•U/S is confirmatory'(enlarged kidneys, multiple cyststhroughout renal parenchyma,increased

cortical thickness,splaying of renal calyces)

•CT abdomen with contrast (for equivocal cases,occasionally reveals more cystic involvement)

•MR1 for kidney volume measurement

•gene linkage analysis for PKDI for asymptomatic carriers

•Cr, BUN, urine R&M (to assessfor hematuria)

Treatment

•goal: to preserve renal function by prevention and treatment of complications

•tolvaptan has been used to slow'decline of renal function, however its use has been limited by side

effects

•educate patient and family about disease,its manifestations,and inheritance pattern

•genetic counselling:transmission rate 50% from affected parent

•prevention and early treatment of urinary tract and cyst infections(avoid instrumentation of GU

tract)

•TMP/SMX, ciprofloxacin: able to penetrate cyst walls, achieve therapeutic levels

•adequate hydration to prevent stone formation

•avoid contactsports due to greater risk of injury to enlarged kidneys

•screen for cerebral aneurysms if family history of aneurysmal hemorrhages

•monitor blood pressure and treat HTN w’ith ACE1

•dialysis or transplant for ESRD (disease does not recur in transplanted kidney)

•may require nephrectomy for symptomatic relief of pain or due to recurrent infections +

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NP39 Nephrology Toronto Notes 2023

Autosomal Recessive Polycystic Kidney Disease

• I in 20000 incidence

• prenatal diagnosis by enlarged kidneys (due to cystic dilatation of the collecting ducts); if significant

in ulero can result in Potter sequence

perinatal death from respiratory failure

• associated with hepatic fibrosis

• patients who survive perinatal period develop CHI'

, HTN, CKD, portal hypertension

• treated with dialysis, kidney, and/or liver transplant

Medullary Sponge Kidney

• common, autosomal dominant, usually diagnosed in 4th-5th decades

• multiple cystic dilatations in the collecting ducts of the medulla

• renal stones, hematuria, and recurrent UT'

Is are common features

• an estimated 10% of patients who present with renal stones have medullary sponge kidney

• nephrocalcinosis on abdominal x-ray in 50% patients, often detect asymptomatic patients incidentally

diagnosis: contrast filled medullary cysts on 1VP leading to characteristic radial pattern (

“

bouquet of

flowers”),

“Swiss cheese"appearance on histological cross-section

• treat UTIs and stone formation as indicated

• does not result in renal failure

End Stage Renal Disease

Definition

• ESRD represents an irreversible decline in kidney function requiring renal replacement therapy

• no definite definition, but glomerular filtration rate less than 15 mL/min/ 1.73 m 2

body surface area, or

those requiring dialysis irrespective of glomerular filtration rate

Risk Factors

• amount of daily proteinuria (strongest predictor of progression to ESRD)

• hypertension, age, history of chronic renal insufficiency, DM, heroin use, tobacco, analgesic

use, ethnicity (increased incidence in Black individuals), lower socioeconomic status, obesity,

hyperuricemia, and family history of kidney disease

Presentation of End Stage Renal Disease

1. Volume Overload

• due to increase in total body Na •content

• signs: weight gain, HTN, pulmonary, or peripheral edema

2. Electrolyte Abnormalities

• high

« K + (decreased renal excretion, increased tissue breakdown)

PO4

3“

(decreased renal excretion, increased tissue breakdown)

• Ca 2+ (rare;happens during recovery phase after rhabdomyolysis-induced AKl or in settings

where hypercalcemia contributes to renal failure, such as in multiple myeloma or sarcoidosis)

uric acid

• low

Na 1

(failure to excrete excessive water intake)

Ca 2+ (decreased vitamin D activation,hyperphosphatemia,hypoalbuminemia)

HC03 ‘

(especially with sepsis or severe heart failure)

3. Uremic Syndrome

• manifestations result from retention of uremic toxins as well as hormone deficiencies

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CNS: headache,lethargy,somnolence,

contusion,asterixis,hyporellexia PUS

wristdrop

Asterixis

Gl: decreased taste

footdrop RESPIRATORY:shortness of

breath,pleuritic chest pain

CVS: pericardial

friction rub

ENDOCRINE:weight loss,

amenorrhea,

decreased libido

Gl: anorexia, _

nausea,vomiting

SKIN:pruritus,pallor.(

yellow discolouration \

GU: irritative and/or

obstructive urinary tact

symptoms,hematuria,

palpable bladder

neuropathy

MSK nocturnalmuscle

cramps,muscle weakness J

•i

Figure 20. Signs and symptoms of end stage renal disease

Complications

•

(.

'

NS: decreased LOC,stupor,seizure

•cardiovascularsystem: cardiomyopathy, CHI', arrhythmia, pericarditis, atherosclerosis

•Gl:peptic ulcer disease, gastroduodenitis, AVM

•hematologic: anemia, bleeding tendency (platelet dysfunction), infections

•endocrine

• decreased testosterone, estrogen, progesterone

• increased 1-SH, LH

•metabolic

•renal osteodystrophy:secondary'increased PTH due to decreased Ca -

+ , high PO-t*-, and low active

vitamin D

• osteitis fibrosa cystica

• hypertriglyceridemia, accelerated atherogenesis

• decreased insulin requirements, increased insulin resistance

•dermatologic: pruritus, ecchvmosis, hematoma, calciphylaxis (vascular Ca -'

deposition )

Treatment

•dialysis is the preferred treatment for ESRl)

•initiation of chronic dialysis has major implications on patients and healthcare system

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Renal Replacement Therapy How

G

to Write Dialysis Orders

(MUST BE INDIVIDUALIZED)

• Filter Type (e.g.F80)

• Length (e.g.4 h 3x/wk or 2 h daily)

• 0Blood Flow (max 500 cc.'rnin)

• Ultrafiltration (e.g.2L or to target

dry weight)

• Na+140 (can be adjusted by starting

at155 and “ramping" down to

minimize cramping)

• K'

(based on serum K)

Serum K+Diatysate

Dialysis

Indications for Dialysis in Chronic Kidney Disease

Table 17. Indications for Dialysis

Absolute Indications Relative Indications

Volume overload* 4-6 i 5

Hyperkalemia*

Severe metabolic acidosis'

Neurologic signsor symptoms of uremia (encephalopathy,

neuropathy,seizures)

Uremic pericarditis

Refractory accelerated HIM

Clinically significant bleeding diathesis

Persistent severe N/ V

Anorexia

Decreased cognitive functioning

Profound fatigue and weakness

Severe anemia unresponsive to erythropoietin

Persistent severe pruritus

Restless leg syndrome

3.54 2.5

<3.5 3.5

. Ca 2*1.25

. HCOJ - 40

• Heparin(none,tight [SOO U/h] or full

[1000 U/hD

• IV fluid to support BP (e.g. NS)

'Unresponsive to medications

• decision to start dialysis in ESRD should be symptom driven or when GTR reaches approximately <10

mL/min

hemodialysis:blood is filtered across a semipermeable membrane removing accumulated toxic

waste products,solutes, excess fluid (ultrafiltration), and restoring buffering agentsto the

bloodstream

available as intermittent (e.g. 3-6x/wk), CVVHD, or SLED which are in-hospital treatments

can be delivered at home or in-centre, nocturnal

vascular access can he achieved through a central line, an artificial AV graft, or an AV fistula

• patients with CKD should he referred forsurgery to attempt construction oi a primary AV fistula when

their e(ilR is <20 ml./min, the serum Cr level quoted as >350 pmol/ L, or within 1 y r of an anticipated

need

• check Kidney failure Risk Equation, which provides the 2 and 5 year probability of treated kidney

failure for a potential patient with CKD stage 3 to 5

• peritoneal dialysis: peritoneum acts as a semipermeable membrane similar to hemodialysisfilter

advantages:independence,fewer stringent dietary restrictions, better rehabilitation rates

• available as continuous ambulatory (CARD; 4-5 exchanges/d) or cyclic (CCPD; machine carries

out exchanges overnight)

• refer patients with chronic renal disease to a nephrologist early on to facilitate treatment and plan in

advance for renal replacement therapy (RRT)

When to Initiate Dialysis

CrCI <20 mL/min

• Educate patient regarding dialysis:

if not a candidate for peritoneal

dialysis,make arrangements for AV

fistula

CrCI <15 mL/min

• Weigh risk and benefits for inilialing

dialysis

CrCI <10 mL/min

• Dialysis should be initialed

NOTE

• Cockcroft-Gault equation (or MDRD

equation) should be used to measure

kidney function

• Monitor for uremic complications

• Significant benefits in quality of life

can occur if dialysis started before

CrCI<15 mL/min

• It is unclear whether patients who

start dialysis early have increased

survival

• A preemptive transplant can be

considered if patient is stable,in

order to avoid dialysis

Table 18. Peritoneal Dialysis vs. Hemodialysis

Peritoneal Dialysis Hemodialysis

Rale Slow fast Sourrt:NjtxwilUOny fwoMionKidney Ohvasu

Outcome

*

Ou

-

llrty MTalrrt location Home

Osmotic pressure via dextrose dialysale

Concentration gradient and convection

Peritoneum

Indwelling catheter in peritoneal cavity

Infection at catheter site

Bacterial peritonitis

Metabolic effects of glucose

Difficult to achieve adequateclearance in patients

with large body mass

Hospital (usually)

Hydrostatic pressure

Concentration gradient and convection

Semi-permeable artificial membrane

Line from vessel to artificial kidney

Vascular access (clots,collapse)

Bacteremia

Bleeding due to heparin

Hemodynamic stress of extracorporeal circuit

Disequilibrium syndrome (headache,cerebral edema,

hypotension,nausea,muscle crampsrclalcd to solute/

water fluxover short time)

Comorbidities,no renal function

Residual tenal function not as important

History ol abdominal surgery

Ultrafiltration

Solute Removal

Membrane Commonly Used Immunosuppressive

Drugs Method

Complications Calcineurin inhibitors

Cyclosporine

Tacrolimus

Antiproliferative medications

Mycophenolate mofeti!

Azathioprine

Other agents

Sirolimus

Prednisone

Anti-lymphocyte antibodies

Thymoglobulin

Basiliximab

Preferred When Residua! renal lunclion

Success depends on presence of residualrenal

function

Hemodynamic instability

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Indications for Dialysis

(Refractory to Medical Therapy)

AEIOU

Acidosis

Electrolyte imbalance (K+)

Intoxication (AKI)

Overload (fluid)

Uremia (encephalopathy,pericarditis,

urea >35-50 mM)

+

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XP42 Nephrology Toronto Notes 2023

Renal Transplantation <§>

IntravenousIron in Patients Unitergoing

Maintenance Hemodialysis

HE JM 2019:380:447 4S8

Purpose: To assesstlx use ol high doses of iron in

patients undergoing hemodialysis.

Study 1.1 , ti centre , open abel trial with blinded

endpoint evaluation.

Population:2141 adu Its with ESftO m whom

maintenance hemodialysis wasinitiated no more than

12 mo prior were randoriied to high-dose IViron

(medan 264 mg monthly) administered proactively

<1.093) or low-doseIV non (median I4S rg monthly|

administered reactrvety (1.048).

Outcome: Primary errdport was nonfatal myocardial

infarction , nonfatal stroke, hospitaliiabon for head

failure,or death.

Results: 29.3% ol patentsin the high dose gioup

had a primary endpomtevent, compared to 32.3%

in the low-dose group.Patients In the high-dose

group had a lower median monthly dose of an

erythiopmesis-stimulating agent compaiedlo the

low-dose gioup I29.75J IU vs.3S.80SIU).

Conclusions:4 high-dose IV iron reg men

administered proactively in patients undergoing

hemodialysis issuperior to a low -dose regimen

administered leacthrely.

•provides maximum replacement ofGFR

•preferred modality of RRT in CKD, not AK1

•best way to reverse uremic signs and symptoms

renal transplantation has been shown to have improved long-term patient survival and greater

quality of life over dialysis

•native kidneys usually left in situ

•2 types:deceased donor,living donor (related or unrelated)

•living donor transplants have been shown to have better short- and long-term outcomes than deceased

donor transplants

•kidney transplanted into iliac fossa, transplant renal artery anastomosed to external iliac artery of

recipient

•induction immunosuppression with IV thymoglobulin or basiliximab, followed by maintenance oral

immunosuppression with an oral immunosuppression cocktail ( usually corticosteroids, calcineurin

inhibitor, anti-metabolite)

•long-term monitoring of cyclosporine and tacrolimuslevels are required

• 1 yr renal allograft survival rates >90%

Complications

•41 cause of mortality in transplanted patients is cardiovascular disease

• increased risk of infections (bacterial, viral, fungal, opportunistic)

•new-onset DM (often due to prednisone and calcineurin inhibitors, especially tacrolimus)

•graft rejection (cellular or humoral)

•acute rejection: rise in Cr,fever, hematuria,graft site tenderness, oliguria, although symptoms are

very uncommon

•early allograft damage caused by episodes of acute rejection and acute peritransplant injuries

•transplant glomerulopathy from antibody injury

•cyclosporine or tacrolimus nephropathy (see Small Vessel Disease,\, P32)

•de novo GN (membranous, IgA, MPGN)

•BK virus (polyoma virus) nephropathy can result from over-ininiunosuppression and lead to graft loss

•leading causes of late allograft loss: interstitial fibrosis/tubular atrophy and death with functioning

graft

•depends on immunologic and nonimmunologic factors (HTN, hyperlipidemia, age of donor, quality of

graft, new onset DM)

•infections (CMV, B) P, and other opportunistic infections usually occur between 1 and 6 mo posttransplant)

•malignancy (skin cancer, Kaposi’ssarcoma, non-Hodgkin’slymphoma)

Survival Benefit with Kidney Transplants from

HIA Incompatible live Donors

HE JM 2016:374:940-950

Purpose:loassess whether there is a survival

advantage to receiving a kidney from HUincompatible donors com pored to lemiirvng on the

waitv.g list lot a possible matched deceased donor

•

Study:Retrospective,multi-centre analysis

Population: 1025 ind nr duals who recened

HU i ncompnt

'

liie live donor kidneys compaied

to two different controls:individuals waitngand

possibly leceiving a deceased donor kidney|N A125).

or individuals ultimately oolieceiving a kidney

transplant (N'

512S|.

Outcome: Survival, tracked loi up to 8 years.

Results: Indiv duals who received HU incompatible

Kidneys had increased survival compared to either

control group for time points at1year.5 years,and

8 years post-transplant (P« 0.001). titer 8 years

noo-matched kidney recipients had J6.S% survival

conpaied to 43.9% lor individuals who ultimately did

not receive a kidney transplant.Survival advantage

wassignificant regardless of how the recipient antiHU ontibodies were detected.

Conclusions'

Individuals who received HU

incompatible kidneys had significantly improved longterm survival com pared to in dividuals w ho waited fur

compatible deceased donor kidneys.

r

^ L J

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