Renal Impairment due to Intravenous Drug

Addiction: A Case Report

By

Dr Azam Arzoo

M.B.B.S ( Bangladesh) Dissertation for the award of (MMed Sci) in Nephrology

Sheffield Kidney Institute

University of Sheffield

Supervisor

Professor A M El Nahas Professor of Nephrology, University of Sheffield

Sheffield Kidney Institute, Northern General Hospital

Sheffield - United Kingdom

September 2007

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CONTENTS    PAGES 

  List of abbreviations     03‐04 

  List of table 

Table ‐1 

Table ‐2 

Table ‐3 

Table ‐4 

Table‐5 

 

Findings of Blood Tests for Specific Types of Acute Kidney Injury

Findings on Urinalysis in the Broad Categories of Acute Kidney Injury 

Diagnostic Indices in Acute Kidney Injury

Differential Diagnosis of Acute Kidney Injury

Supportive therapies for renal dysfunction 

 

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13 

17 

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24 

  List of figure 

Figure‐1 

 

Diagnosis and treatment of acute renal failure. 

 

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  Acknowledgement    05 

   Dedication    06 

   Abstract    07 

  Chapter‐I 

Introduction 

   

07‐09 

  Chapter‐II 

Clinical approach 

   

09‐16 

  Chapter‐III 

Differential diagnosis 

Literature review

Management 

   

17‐24 

19‐24 

24‐25 

  Chapter‐IV 

Discussion 

Conclusion 

References 

   

26‐29 

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30‐35 

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List of abbreviations

AA: Amyloid A

ACE: Angiotensin-converting enzyme

ACEi: Angiotensin Converting Enzyme Inhibitor

AIN: Acute interstitial nephritis

AKI: Acute Kidney Injury

ARB: Angiotensin Receptor Blocker

ART: Antiretroviral therapy

ATN: Acute Tubular Necrosis

BP: Blood Pressure

CAPD: Continious Ambulatory Peritoneal Dialysis

CKD: Chronic Kidney Disease

EM: Electron microscopy

ESRD: End-stage renal disease

ESRD: End stage of Renal Disease

FSGS: Focal segmental glomerulosclerosis

GFR: Glomerular filtration rate

GFR: Glomerular filtration Rate

GN: Glomerulonephritis

GN: Glomerulonephritis

HD: Haemodialysis

HIV: Human immunodeficiency virus

HSP: Henoch-Schönlein purpura

IC: Immune complex

IDUs: injecting drug users

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IHD: Ischaemic Heart Disease

MPGN: Membranoproliferative glomerulonephritis

NGAL: Neutrophil gelatinase-associated lipocalin

NP: Nephropathy

NSAID: Non Steroidal Anti Inflamatory Drug

NSAID: Nonsteroidal anti-inflammatory agent

PD: Peritoneal Dialysis

PSGN: Poststreptococcal glomerulonephritis

RPGN: Rapidly progressive glomerulonephritis

RRT: Renal replacement Theraphy

S.Cr: Serum Creatinine

SKI: Sheffield Kidney Institute

SLE: Systemic lupus erythematosus

 

 

 

 

 

 

 

 

 

 

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ACKNOWLEDGEMENT

First and foremost, is praised to Almighty ALLAH, the creator of the world, the beneficent and

the most merciful. Without his help and guidance, this work, and every other work, would not be

possible

My sincerest appreciation to Prof AM EL NAHAS, for affording me the opportunity to

pursue this thesis in the department of Nephrology, Sheffield Kidney Institute, University of

Sheffield and for his guidance and supervision all through the preparation of this thesis.

I would like to thank Dr Lutfi, Dr Kossi, Dr Brown, Dr Brenann, Dr Kawar, Dr Othman,

Dr Parvez, Dr Amino Bello and Dr Ghada Said M. Omar

Finally, my deepest gratitude is due to my parents, brothers and sister for their love,

prayer and continues encouragement throughout the course.

 

 

 

 

 

 

 

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Dedicated to

My mother, Late Tasliman Nisa who sacrifices her whole life to make me a doctor

and dreamt for me to get specialized degree from England and her wish was that

“Before being a good doctor I should be a good human being”

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Abstract A 28 year old intravenous drug addict has presented to the Sheffield Kidney Institute with

impaired kidney function (serum creatinine 215 umol/l) and heavy proteinuria (4.5 g/24h).

Physical examination is normal with the exception of peripheral oedema. The most likely

diagnosis is; acute kidney injury as a consequence of the history of drug addiction. The

Management approach would be to focus on immediate treatment of the acute kidney injury,

however long term drug withdrawal rehabilitation plan has to be addressed.

Chapter I Introduction

Drugs are administered through different routes. Injection of the drug directly into the

bloodstream (intravenously) is the most dangerous route; this is because the pathogens can be

introduced into the body via the blood steam through the contaminated shared needles due to the

lack of sterile preparation and injection techniques. Medical problems may also arise from the

damage to body organs caused by the drugs themselves (i.e. the direct effect of the drugs on the

body organs due to drug overdose). Another problem could be the impurity of the injected drugs;

that may contain some substances such as talc, lactate, or quinine which complicate the condition

and might increase the risk of infection (Landry, 1994; Joyce et al., 2005). Drug addicts most

commonly use the intravenous route.

Prevalence of drug use amongst the adult population in the United Kingdom is estimated

to be 53 %. The highest prevalence level for lifetime drug use is now amongst 16 to 34 year olds.

In addition, young people aged 16 to 24 years old continue to show the highest levels of recent

and current use (Eaton, 2005). The mortality rate for injecting drug users (IDUs) from all causes

is estimated to be 3-4% per year (Baciewicz, 2005).

Many local and systemic complications are known to be associated with IV drug use,

most commonly the transmission of infectious diseases such as hepatitis and human

immunodeficiency virus (HIV) via needle sharing. The most commonly injected drugs are heroin

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and cocaine. Amphetamines, buprenorphine, benzodiazepines, and barbiturates are also used. It

was reported that any water-soluble drug may be injected IV (Baciewicz, 2005).

Local complications that are known to be associated with IV administration of drugs

include; abscess, cellulitis, septic thrombophlebitis, local induration, necrotizing fascitis, gas

gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (eg,

broken needle parts). The most common reported infectious organisms are; Staphylococcus

aureus or Staphylococcus epidermidis, streptococci, and gram-negative bacilli. The well reported

systemic problems associated with IV drug use in addition to the HIV infection and hepatitis (B

or C) mentioned above are; pneumonia and lung abscess from septic emboli to the lung, acute

and subacute bacterial endocarditis, group A beta-hemolytic streptococcal septicemia,

osteomyelitis, septic arthritis, candidal and other fungal infections, tetanus, clostridial

myonecrosis, malaria, and amyloidosis. The endocarditis that occurs in IDUs involves the right-

sided heart valves; a recent review found no explanation for this predilection (Frontera and

Gradon, 2000). A rare case of needle embolization to the lung has been reported (Baciewicz,

2005).

Furthermore, IV drug abuse may also result in numerous acute and chronic renal

consequences. Acute effects include: Oliguria (Goodman & Gilman, 1990), acute renal failure

mainly. While chronic effects include: glomerulonephritis of immunological origin, chronic

glomerulonephritis with segmental, focal and diffuse glomerulosclerosis, which may lead to

terminal renal failure in one to four years (Cunningham et al., 1980). Segmental hyalinosis,

nephrotic syndrome and renal amyloid, glomerulonephritis (may be membranous), proliferative

or membrano-proliferative Good pasture syndrome have been reported to be associated with IV

drug addiction (Uzan et al., 1988; Vassals & Pezzano, 1987). Pyuria and proteinuria are

frequently reported (Duberstein & Myland Kaufman, 1971), as well rhabdomyolysis due to a

direct effect of drug injection (D'Agostino & Ernest, 1979; Conti et al., 1990). The explanation

was given that rhabdomyolysis is due to the compression of muscle during prolonged coma

aggravated by hypoxia, acidosis and hypovolemia (Pearce & Cox, 1980; Ellenhorn & Barceloux,

1988,Vassals & Pezzano, 1987; Uzan et al., 1988). Renal damage may progress to terminal renal

insufficiency (Cunningham et al., 1980). Genetic factors (African Carribean), and impurities in

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the heroin (direct toxicity, or immunogenicity) have been suggested to cause renal insufficiency

(Cunningham et al., 1980). There is no experimental evidence concerning the effects of repeated

injection of unsterile heroin on renal function. In humans, such injections generally introduce a

variety of antigens, and can lead to circulating immune complexes (Uzan et al., 1988).

Chapter II

Clinical Approach A 28 year old addict boy admitted to the Northern General Hospital, Sheffield Kidney

Institute, with an impaired kidney function following intravenous drug abuse. The patient

laboratory results showed increased serum creatinine level of 215 umol/l and heavy proteinuria

(4.5 g/24h). All physical examination is normal with the exception of peripheral oedema. The

patient showed heavy proteinuria which is strong marker of nephritic syndrome and glomerular

disease. On the other hand, serum creatinine is a poor marker of nephrotic syndrome (Branten et

al., 2005).

Approach to the Patient with Renal Disease-Associated Proteinuria and elevated serum creatinine

Once it has been established that the patient has constant proteinuria, regardless of

position and functional status, a careful evaluation is needed, starting with a detailed history and

physical examination. The history should identify the presence of pre-existing systemic diseases,

particularly diabetes mellitus, SLE, hypertension, and certain infections that are associated with

glomerular pathology, such as hepatitis, syphilis, or endocarditis. A drug history is also essential.

Intravenous drug abuse has been associated with a pattern of renal disease that morphologically

resembles but is not identical to focal segmental glomerulosclerosis (Rao et al., 1974). Heavy use

of nonsteroidal anti-inflammatory drugs can be associated with prominent rates of proteinuria

(Brezin et al., 1979). The presence of a rash or arthritis which suggests a vasculitis or systemic

disease should be carefully evaluated. Significant weight loss may be an indication of an occult

malignancy, which can be associated with a glomerulopathy. The presence of a family history of

familial renal disease, particularly with certain rare structural defects, such as deformities of the

nails and patella, are associated with heavy proteinuria (nail-patella syndrome) (Hoyer et al.,

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1972). In addition, HIV infection may be associated with a form of nephropathy and progressive

renal disease (Bourgoignie et al., 1988).

During physical examination particular attention should be given to the patient’s blood

pressure and retinal findings. Other elements to be considered are the heart size and any unusual

skin lesions such as palpable purpura suggestive of vasculitis or interstitial nephritis, periorbital

lesions (“racoon’s eyes”) may suggest the presence of amyloid. The funduscopic examination is

particularly important because it may reveal early diabetic retinopathy, even in the patient

without the diagnosis of diabetes mellitus, however in this case this is unlikely because of the age

of the patient. Likewise, the presence of a rash may suggest a drug reaction, SLE, vasculitis, or

cryoglobulinemia which may all cause proteinuria. Enlargement of the lymph nodes,

hepatosplenomegaly may be a consequence of certain lymphomas, particularly Hodgkin disease,

which can be associated with minimal change disease (Dabbs et al., 1986) and membranous

glomerulonephritis has been reported to be associated with several different malignancies,

including lung and colon cancer (Striker et al., 1985), although a rectal examinations and testing

for occult blood in the stool may be valuable, colonoscopy in the evaluation of choice for such

malignancies, however in this case may not be necessary due to the unlikely presence of such

malignancies that usually associated with older age.

Blood and urine tests can provide supporting data. BUN and serum electrolyte, creatinine,

calcium, phosphorus and albumin levels, as well as a complete blood count with differential,

should be obtained in this patient. The degree of renal function should be determined by

measuring serum creatinine or estimation of GFR by e.g. the use of the Cockcroft and Gault

formula and 24 hrs of creatinine clearance, this also should include 24 hrs protein urine

excretions. The most simple and safe clinical index of renal function is 24 hour urine creatinine

clearance, which will approximates glomerular filtration rate. In certain circumstances, other

blood tests are indicated (Table 1). All patients should have the following urine studies: dipstick

test, microscopy, sodium and creatinine levels, and urine osmolality determination (Agrawal and

Swartz, 2000).

On the basis of laboratory studies, the urinary sediment helps to distinguish whether

serious renal disease is present (Table 2) (Agrawal and Swartz, 2000). The presence of active

urinary sediment suggests a glomerular or interstitial inflammatory immune response and greater

likelihood of an associated reduction in renal function. In addition, serological tests for hepatitis

(both B and C), HIV, and syphilis may be helpful (Wingo and Clapp, 2000).

TABLE 1

Findings of Blood Tests for Specific Types of Acute Kidney Injury

Findings on blood tests Diagnoses to consider

Elevated uric acid level Suggestive of malignancy or tumor lysis syndrome leading to uric acid crystals; also seen in prerenal acute renal failure

Elevated creatine kinase or myoglobin levels Rhabdomyolysis

Elevated prostate-specific antigen Prostate cancer

Abnormal serum protein electrophoresis Multiple myeloma

Low complement levels Systemic lupus erythematosus, postinfectious glomerulonephritis, subacute bacterial endocarditis

Positive antineutrophilic cytoplasmic antibody Small-vessel vasculitis (Wegener's granulomatosis or polyarteritis nodosa)

Positive antinuclear antibody or antibody to double-stranded DNA

Systemic lupus erythematosus

Positive antibody to glomerular basement membrane

Goodpasture's syndrome

Positive antibodies to streptolysin O, streptokinase or hyaluronidase

Poststreptococcal glomerulonephritis

Schistocytes on peripheral smear, decreased haptoglobin level, elevated lactate dehydrogenase level or elevated serum bilirubin level

Hemolytic uremic syndrome or thrombotic thrombocytopenic purpura

Low albumin level Liver disease or nephrotic syndrome

Modified from Agrawal and Swartz, 2000

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With new early markers for renal injury such as NGAL (neutrophil gelatinase-associated

lipocalin or lipocalin-2), physicians can initiate proper management of acute renal failure within

hours rather than days of the insult. The lack of an early diagnostic marker for acute renal failure

has held back improvements in treatment methods (Miklaszewska et al., 2006; Trachtman et al.,

2006).

High serum creatinine concentrations were defined by a cutoff value of ≥115 umol/L in

women and ≥133 umol/L in men based upon prior studies. A creatinine level of 120 to 150 umol

/L represents a loss of filtration function of more than 50%. Early referral for such cases will

avoid irreversible renal disease to occur (Mendelssohn et al, 1999).

Heavy proteinuria generally reflects the presence of significant glomerular pathology and

nephrotic syndrome. ‘Nephrotic range’ proteinuria (>3.0g/24h) is always glomerular in the

absence of urinary infection. Proteinuria is also an important prognostic indicator for the

progression of chronic renal damage (EdRen Handbook, 2007). Nephrotic syndrome leads to

hypoalbuminemia, edema, and hyperlipidemia that in turn result in diverse complications, such as

increased thromboembolic events, renal tubular dysfunction, and increased susceptibility to

infections (Wingo and Clapp, 2000).

When considering persons with nephrotic-range proteinuria, it is useful to determine

whether the proteinuria is present in association with active urinary sediment (containing cells

and/or casts) or whether it reflects isolated proteinuria. If there is active urinary sediment, one is

usually either dealing with a primary glomerulonephritis or a glomerulonephritis secondary to a

systemic disease. The most likely systemic diseases that produce proteinuria with an active, or

nephritic, urinary sediment are SLE, vasculitis, endocarditis, and cryoglobulinemia (Wingo and

Clapp, 2000)

TABLE 2 Findings on Urinalysis in the Broad Categories of Acute Kidney Injury

Type of renal failure Findings on urinalysis

Prerenal acute renal failure

Scant; few hyaline casts

Postrenal acute renal failure

Scant; few hyaline casts, possible red cells

Acute tubular necrosis Epithelial cells, muddy-brown, coarsely granular casts, white blood cells, low-grade proteinuria

Allergic interstitial nephritis

White blood cells, red blood cells, epithelial cells, eosinophils, possible white blood cell cast, low to moderate proteinuria

Glomerulonephritis Red blood cell casts, dysmorphic red cells, moderate to severe proteinuria

Adapted from Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448-60.

If this patient has nephrotic range proteinuria but the examination of the urinary sediment

is largely unremarkable, one should consider certain systemic diseases as a possible cause. The

most common of these is diabetic nephropathy and a careful examination for diabetic retinopathy

may lead to a presumptive diagnosis (because of the age this is unlikely). SLE may occasionally

present with a secondary membranous glomerulonephritis and isolated proteinuria. Serologic

testing may support the diagnosis before overt clinical symptoms of SLE are present. Although

nephrotic-range isolated proteinuria is rarely observed in uncomplicated hypertension, it may be

seen in malignant hypertension. The presence of hypertension and proteinuria, particularly if

associated with renal insufficiency with unremarkable urinary sediment, should lead one to test

for the presence of lead and other heavy metal toxicity. Also, plasma cell dyscrasias and

amyloidosis may present with isolated nephrotic-range proteinuria. If these secondary causes of

isolated nephrotic-range proteinuria are excluded, then the likely cause of the proteinuria is a

primary glomerular disease; membranous glomerulonephritis, focal segmental

glomerulosclerosis, or minimal change disease (also called lipoid nephrosis) are the most likely

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causes. IgA nephropathy may present with nephrotic-range proteinuria, although hematuria is a

more common form of presentation. The diagnosis of these conditions usually should be

confirmed by renal biopsy (Wingo and Clapp, 2000).

Acute kidney injury (AKI) is frequently defined as an acute increase of the serum

creatinine level from baseline (i.e., an increase of at least 0.5 mg per dL [44.2 µmol per L]) or a

50 % increase in the creatinine level above the baseline value, a 50 % decrease in the baseline-

calculated glomerular filtration rate (GFR) (Singri et al., 2003). This finding is matching with the

laboratory result of this case which suggesting a case of acute kidney injury. Using a step-by-step

clinical approach, physicians can determine the cause of acute kidney injury in most patients

(Figure 1).

Acute kidney injury pathophysiologic changes are categorized into; Pre-renal, intrinsic and

postrenal.

1. Prerenal represents 60 to 70 % of the cases. It is characterized by hypoperfusion of the kidney

without compromise of the integrity of the renal parenchyma

a. Hypovolemic – Hemorrhage, vomiting, diarrhea, burns, surgical drains, diuresis

(drugs, osmotic), third spacing (eg/ pancreatitis, hypoalbuminemia)

c. Decreased ECV – CHF, nephrotic syndrome, hepatorenal

d. Systemic vasodilatation – Sepsis, anaphylaxis, antihypertensives

e. Drugs – ACE inhibitors, NSAIDS, radiocontrast

2. Renal AKI represents 25 % of the cases. It is directly affects renal parenchyma. Further

categorized into vascular, glomerular, tubular, and tubulointerstitial.

a. Vascular

i.Macrovascular – Renal artery stenosis, thromboembolism, atherosclerotic

plaque, dissection, renal vein thrombosis

ii.Microvascular – Hemolytic uremic syndrome (HUS), thrombotic

thrombocytopenic purpura (TTP), HELLP

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b. Glomerular – RPGN, Wegener’s granulomatosis, Goodpasture’s syndrome,

microscopic polyangiitis, postinfectious GN, membranous nephropathy, lupus

nephritis, Henoch-Schölein purpura

c. Tubular/ATN

i.Ischemia – Surgery, hemorrhage, arterial or venous obstruction, ACEI,

NSAIDs, radiocontrast, amphotericin B

ii.Exogenous toxins – Radiocontrast, aminoglycosides, β-lactam

antibiotics, amphotericin B, cyclosporine, sulfonamides, heavy metals,

methotrexate

iii.Endogenous toxins – Rhabdomyolysis, hemoglobinuria, myoglobinuria,

uric acid crystals, myeloma protein, hypercalcemia

d. Interstitial

i.Allergic interstitial nephritis – NSAIDS, β-lactam antibiotics,

sulfonamides, ciprofloxacin, thiazide diuretics, allopurinol

ii.Infection – Acute pyelonephritis

iii.Infiltration – Sarcoid, Lymphoma

3. Postrenal AKI represents 5% of the cases. It is associated with urinary tract obstruction

– BPH, bladder cancer, renal calculi, retroperitoneal fibrosis and urethral stricture or

valves. (Needham, 2006; Agrawal and Swartz, 2000; Brady and Singer, 1995).

By interpenetrating the laboratory results for this patient, it can be concluded that the case

is acute kidney injury. Considering the IV drug abuse is a causative factor for AKI due to renal

effect. Heavy asymptomatic proteinuria associated with presence of oedema suggested nephrotic

syndrome or a glomerular disorder, caused either by a primary renal disease or renal involvement

as a result of systemic disease.

Acute Kidney Injury

FIGURE 1. Algorithm for the diagnosis and treatment of acute renal failure. (HELLP = hemolysis, elevated liver enzymes and low platelets.) Modified from Agrawal and Swartz, 2000

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Chapter III Differential Diagnosis

The diagnosis of this case is highlighted by the obvious acute renal system involvement,

the indicators are; the elevation in serum creatinine level and heavy and persistent proteinuria.

Patients with asymptomatic proteinuria usually have no signs, but in more severe cases, such as

with nephrotic syndrome, there may be oedema, ascites , hydrocoeles and pleural effusions as a

result of decreased oncotic pressure. Nephrotic syndrome consists of proteinuria,

hypoalbuminaemia, hyperlipidemia and oedema. Moreover an elevated serum creatinine level can

be acute or chronic. An acute rise in the serum creatinine level (during a period of hours or days)

has been called acute renal failure. This term has been replaced by acute kidney injury, defined as

either an absolute increase in the serum creatinine level of more than 0.3 mg per deciliter (26.5

μmol per liter) or a percentage increase of more than 50% (by a factor of 1.5 from baseline)

(Rabb and Colvin., 2007). Table 3 shows the diagnostic marker for AKI.

TABLE 3 Diagnostic Indices in Acute Kidney Injury

Index

Prerenal Postrenal

Tubular Injury

AGN

U/P osmolality

> 1.5

1 to 1.5

1 to 1.5

1 to 1.5

Urine Na (mmol/L)

< 20

> 40

> 40

> 30

Fractional excretion of Na (FENa)*

Renal failure index

< 0.01

< 1

> 0.04

> 2

> 0.02

> 2

< 0.01

< 1

*U/P Na ÷ U/P creatinine, †Urine Na ÷ U/P creatinine ratio, AGN = acute glomerulonephritis; U/P = urine-to-plasma ratio.

Adapted from Miller TR, et al: “Urinary diagnostic indices in acute renal failure.” Annals of Internal Medicine 89(1):47–50,

1978.

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Causes of acute kidney injury are divided into prerenal, intrarenal, and postrenal factors

(Table 4) (Rabb and Colvin., 2007).

TABLE 4 Differential Diagnosis of Acute Kidney Injury

Types of acute renal failure and underlying problem

Possible disorders

Prerenal acute kidney injury

True intravascular depletion

Sepsis, hemorrhage, overdiuresis, poor fluid intake, vomiting, diarrhea

Decreased effective circulating volume to the kidneys

Congestive heart failure, cirrhosis or hepatorenal syndrome, nephrotic syndrome

Impaired renal blood flow because of exogenous agents

Angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs

Intrinsic AKI Acute tubular necrosis Ischemia

Toxins: drugs (e.g., aminoglycosides), contrast agents, pigments (myoglobin or hemoglobin)

Glomerular disease Rapidly progressive glomerulonephritis: systemic lupus erythematosus, small-vessel vasculitis (Wegener's granulomatosis or polyarteritis nodosa), Henoch-Schönlein purpura (immunoglobulin A nephropathy), Goodpasture's syndromeAcute proliferative glomerulonephritis: endocarditis, poststreptococcal infection, postpneumococcal infection

Vascular disease Microvascular disease: atheroembolic disease (cholesterol-plaque microembolism), thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, HELLP syndrome or postpartum acute renal failure Macrovascular disease: renal artery occlusion, severe abdominal aortic disease (aneurysm)

Interstitial disease Allergic reaction to drugs, autoimmune disease: (systemic lupus erythematosus or mixed connective tissue disease), pyelonephritis, infiltrative disease (lymphoma or leukemia)

Postrenal AKI Benign prostatic hypertrophy or prostate cancer, cervical cancer, retroperitoneal disorders, intratubular obstruction (crystals or myeloma light chains), pelvic mass or invasive pelvic malignancy, intraluminal bladder mass (clot, tumor or fungus ball), neurogenic bladder, urethral strictures

HELLP = hemolysis, elevated liver enzymes, and low platelets. Modified from Friedewald and Rabb 2007.

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The differential diagnosis of this patient‘s impaired kidney function, based upon reviewing

the related-literatures, possibly are: acute kidney injury due to rhabdomyolysis or acute tubular

necrosis, nephrotic syndrome, glomerulonephritis (GN) induced by Staphylococcus aureus from

unsterile injection, endocarditis due to bacterial and fungal infection, membranous nephropathy

due to hepatitis B infection, mesangiocapillary GN due to hepatitis C infection, secondary (AA)

amylodosis due to prolonged parenteral drug use (Miranda et al., 2006), heroin-associated

nephropathy (HAN), or HIV-associated nephropathy (HIVAN).

Literature review regarding the different diagnostic possibilities.

The renal complications of drug abuse are also becoming more frequent, and may

encompass a spectrum of glomerular, interstitial and vascular diseases. Although some

substances are directly nephrotoxic, a number of other mechanisms are also involved. These

effects are often chronic and irreversible, but occasionally acute with possible recovery (Crowe et

al., 2000).

There are several renal complications from heroin abuse. Coma from overdose or

underestimated drug potency leads to pressure induced muscle damage and rhabdomyolysis.

Hypotension, hypoxia, acidosis and dehydration may aggravate this. Others have demonstrated

rhabdomyolysis in the absence of coma or evidence of muscle compression, and suggest this

could be due to a direct toxic effect or an allergic response to heroin or the components in impure

heroin (Grossman et al., 1974).

Follow-up studies of heroin addicts indicate an annual mortality of 4.8% (Gunne and

Gronbladh, 1981). The majority of these drugs, or their metabolites, are excreted via the kidney.

To achieve their recreational effects these drugs must cross the blood-brain barrier and many are

highly lipid-soluble; this results in high volumes of distribution with dialysis of little benefit in

overdose (Crowe et al., 2000).

European Renal Association study for 156 heroin addict patients along a period of 23

months showed that l5.5% of them had renal disease. In first group of patient, kidney biopsies

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showed the presence of proliferative glomerulonephritis (GN), diffuse and focal proliferative GN

associated to Staphylococcus aureus endocarditis or sepsis. Clinical presentation included

proteinunia, frequently in a nephrotic range, microscopic hematuria and hypocomplementamia.

Diffuse forms showed no histological differences with the post streptococcal acute GN. Heroin

nephropathy detected among three patients. Two of them showed a focal and segmental

qlomerulosclerosis and the third case had a membranoproliferetive GN. Nephrotic syndrome was

the most frequent presentation form and one of the focal and segmental glomeruloselerosis

patients showed a complete remission after cessation in heroin addiction. Furthermore, acute

tubular necrosis because of sepsis or nephrotoxic drugs, along or acompanning to the previous

lesions, was found in 11 cases. This patients had and oliguric acute renal failure and 10 of' them

dead. Ten patients had serum virus 3 markers but only one of them had positive anti HBsAg

glomerular deposits. It was concluded that heroin addiction is increasing in an important risk of

renal disease. Different histological findings are present in relation to heroin toxicity, its vehicles

and contaminants or more frequently to sepsis. The heroin nephropathy can improve after

discontinuation of' drug addiction. The association to acute renal failure is frequent end has a

high mortality rate (Lopez-Gomez el al., 1985).

There is a high rate of viral, bacterial and fungal contamination associated with

intravenous drug misuse, including heroin (Tuazon et al., 1974), and consequently users are at

risk of a variety of infections. Glomerulonephritis (GN) may be associated with these chronic

infections. Local pyogenic abscesses, due to Staphylococcus aureus, have been associated with

GN, thought to be due to deposition of immune complexes formed in response to the organism.

Bacterial and fungal (Roberts and Rabson, 1975) endocarditis can also cause immune-complex-

mediated GN(Stein, 1990). Hepatitis B has also been associated with GN, usually membranous

and with polyarteritis nodosa. Hepatitis C causes mesangiocapillary GN with associated

cryoglobulinaemia. Secondary (AA) amyloidosis has increased in frequency as a cause of renal

disease in chronic parenteral drug users (Crowe et al., 2000).

In the 1970s and 1980s, heroin-associated nephropathy (HAN) was described, presenting

as nephrotic syndrome and progressing rapidly to end-stage renal failure. Occasionally the

process reversed with discipline from further heroin use. Renal biopsy usually showed a focal

segmental glomerulosclerosis. The pathogenesis of this is unclear; earlier studies suggested that

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heroin, or one of its adulterants, acted as antigen leading to renal deposition of immune

complexes in the kidney (Sreepada Rao et al., 1977). More recent animal studies have shown that

morphine may a direct effect on the glomerulus, causing proliferation of fibroblasts and a

decrease in degradation of type IV collagen (Crowe et al., 2000).

Nowadays, HIV-associated nephropathy (HIVAN) is being diagnosed more frequently

among heroin addicts with HIV infection (D’Agati et al., 1998). HIVAN also presents with

nephrotic syndrome and rapidly progressing renal failure, and it can cause up 38% of end-stage

renal failure (Pastan et al., 1998). Renal biopsy usually reveals characteristic collapsing

glomerular tuft with epithelial cell prominence. Localized segmental sclerosis of the tuft can also

occur (Humphreys, 1995). A recent report of a case of clinical and histological resolution of

HIVAN following treatment with triple antiretroviral therapy and reduction in viral load supports

the hypothesis that the virus has a direct cytopathic effect on the kidney (Wali et al., 1998).

A wide spectrum of renal complications can occur with both acute and chronic use of

cocaine. Except for cocaine-induced rhabdomyolysis, the direct effects of cocaine on the kidney

have received less attention. The pathophysiologic basis of cocaine-related renal injury is

multifactorial and involves changes in renal hemodynamics, changes in glomerular matrix

synthesis, degradation and oxidative stress, and induction of renal atherogenesis (Jaffe and

Kimmel, 2006).

Acute renal failure can occur as a result of rhabdomyolysis (Roth et al., 1988). In one

series 24% of patients seen in an emergency department with cocaine-associated complaints

presented with concentrations of creatine kinase of more than 1000U/l.20 (Welch et al., 1991).

Up to one third of such patients develop acute renal failure (Roth et al., 1988).

Muscle ischaemia caused through prolonged vasoconstriction of intramuscular arteries,

generalized seizures, coma with secondary muscle compression, or direct myofibrillar damage

are different mechanisms of cocaine-induced rhabdomyolysis. Cocaine may be contaminated

with arsenic, strychnine, amphetamine and phencyclidine, which may also cause seizures and

22  

 

rhabdomyolysis (Cregler and Mark, 1986). Moreover, a case of cardiorespiratory arrest was

reported after cocaine and heroin ingestion. The arrest is attributed primarily to hyperkalaemia/

rhabdomyolysis, a recognized consequence of each of these drugs (McCann et al., 2002).

The syndrome of cocaine-induced premature artery disease is well described. Less well

known is that cocaine can cause renal infarction (Sharff, 1984) and atherosclerosis of the kidney

(Fogo et al., 1992)(Di Paolo et al., 1997). However, a recent study of 301 chronic cocaine users

showed no association with chronic hypertension or the development of microalbuminuria

(Brecklin et al., 1998). There may be perhaps a propensity for cocaine to exacerbate pre-existing

renal disease rather than cause de novo disease (Dunea et al., 1995).

Immunologically, cocaine has been shown to cause mesangial proliferation by increasing

the release of interleukin-6 by macrophages, which may be a cause of focal segmental

glomerulosclerosis. Associations of cocaine abuse with renal scleroderma (Lam and Ballou,

1992) and Henoch-Schönlein purpura have also been described (Chevalier et al., 1995).

In experimental animals, MDMA (3,4-methylenedioxymethamphetamine) has been

shown to cause fever even in the absence of strenuous exercise. Unwanted effects may be minor

loss of appetite nausea, vomiting, headaches, trismus and cramps, or serious convulsions,

hyperpyrexia, hepatic dysfunction, rhabdomyolysis, disseminated intravascular coagulation

(Henry et al., 1992) and acute renal failure. (Fahal et al., 1992) The patient with rhabdomyolysis

typically presents with muscle pain and tenderness, and is found to be in acute nephrotoxic renal

failure with hyperkalaemia, hyperphosphataemia, and raised creatine kinase. Myoglobin and

granular casts are found in the urine.

Approximately 70% of injecting drug users has used temazepam at sometime. (Lavelle et

al., 1991). Acute renal failure has been described following inadvertent intraarterial temazepam

injection. This provokes limb ischaemia as a result of particulate embolization and subsequent

rhabdomolysis and myoglobinuria.(Blair et al., 1991) Severe but temporary dialysis-dependent

renal failure was present in 20% of patients in one series (Jenkinson and Pusey ,1994) (Crowe et

al., 2000).

23  

 

Deighan et al., 2000 reported, in retrospective review of dialysis-dependent ARF between

1986–1997, an increase in ARF and non-traumatic rhabdomyolysis associated with drug abuse in

West of Scotland. The incidence of dialysis dependent AKI from rhabdomyolysis due to drug

abuse over a period of 12 years 1986-1991 has increased markedly from 17 cases to 59 cases in

the next 6 years.

The increase in rhabdomyolysis and acute renal failure is likely to be due to the increased

parenteral abuse of drugs such as temazepam. First reports of intravenous abuse of temazepam

came from Glasgow in 1987 (Stark et al., 1987). In November 1989 the formulation of

temazepam was changed to a hard gel in an attempt to discourage misuse. Addicts however

circumvented this problem by heating the `jellies' on a metal spoon and then injecting the melted

substance into an accessible blood vessel. Subsequently a number of reports of ischaemic limbs

after intra-arterial injection of temazepam were published (Blair et al., 1991; Scott et al., 1992)

and in 1994 Jenkinson and Pusey reported two cases of rhabdomyolysis and acute renal failure

following intra-arterial injection of temazepam. All 13 cases reported here occurred after the

change in formulation of the temazepam and this change appears to have contributed to the

increased incidence of acute renal failure from rhabdomyolysis.

The increased longevity of drug users leads to the emergence of new diseases as a result

of chronic bacterial and viral infection. It was reported that secondary AA amyloidosis is a

serious complication of chronic soft tissue infection in intravenous drug users in central London.

Affected individuals invariably presented with nephritic range proteinuria (mean 7.3 g/l, range

0.5–14.8 g/l) and advanced renal failure. A high proportion of patients (85%) had a history of

recurrent deep-vein thrombosis. The reporter speculated that the increasing drug longevity in

users with poor venous access, and the attendant increase in subcutaneous injection and sepsis, is

a major contributory factor in the development of amyloidosis (Connolly et al., 2006).

In summary, a variety of renal diseases may result from the repeated injection of drugs

with the apparently contaminated paraphernalia which drug addicts utilize. First is the focal or

diffuse glomerulonephritis which develops in patients with bacterial endocarditis. Next is the

lesion associated with acute viral hepatitis, characterized by proteinuria of less than 2 gm/day and

focal increase in PAS-positive material in the mesangium. Renal involvement with necrotizing

angiitis has also been reported. Another group of these patients may present with acute renal

failure secondary to myoglobinuria due to muscle injury at the site of self-injection of water

which is apparently used during withdrawal. Finally, nephritic syndrome of no apparent etiology

is gradually becoming recognized as occurring in greater frequency in the drug addict (Eknoyan,

1975).

Management of acute Kidney Injury

24  

 

Management of established acute kidney

injury involves general measures (Table 5)

irrespective of the cause and specific treatments

targeted to the particular cause.

The goal of treatment is to restore kidney

function and prevent fluid and waste from building up

in the body while the kidneys recover. Initial treatment

should focus on correcting fluid and electrolyte

balances and uremia, provide nutritional support, and

prevent or treat complications such as infection

(Hilton, 2006). Since impaired kidney function in

this case is associated with IV drug abuse. Cessation

of nephrotoxins uptake is one of the main supportive

approaches.

TABLE 5 Supportive therapies for renal dysfunction

• Sodium and water prescriptions. • Blood pressure control with ACE

inhibitors, angiotensin receptor blockers.

• Avoidance of nephrotoxins especially drugs, such as NSAIDs, contrast agents.

• Smoking avoidance, low-protein diet (benefit controversial, but not harmful).

Adapted from Cunard R and Kelly CJ. Immune-mediated renal disease. J Allergy Clin Immunol 2003;111:S637-44.

Because acute renal failure is a catabolic state, patients can become nutritionally deficient.

Total caloric intake should be 30 to 45 kcal (126 to 189 kJ) per kg per day, most of which should

come from a combination of carbohydrates and lipids. In patients who are not receiving dialysis,

protein intake should be restricted to 0.6 g per kg per day. Patients who are receiving dialysis

25  

 

should have a protein intake of 1 to 1.5 g per kg per day (Wolfson and Kopple, 1993) (Agrawal

and Swartz, 2000).

In spite of much research, no drug treatment has as yet been shown to limit the

progression of, or speed up recovery from, acute renal failure, and some drugs may be harmful

(Kellum et al., 2001) (Hilton, 2006). The use of furosemide warrants particular mention, as this is

a commonly used and inexpensive intervention. A recent meta-analysis of randomised controlled

trials showed that furosemide is ineffective in preventing and treating acute renal failure and that

high dose may be associated with ototoxicity (Kwok and Sheridan, 2006).

Note that there is no evidence that dopamine is of benefit. There are some reasons to

suspect that it may be potentially harmful as it impairs splanchnic perfusion. Loop diuretics may

increase urine output in those with less severe degrees of renal failure, but there is no evidence

that they improve outcome (requirement for or duration of dialysis, or mortality) and some

evidence that they can be harmful. Most interventions tested in prevention of ARF after

radiographic contrast administration is ineffective or harmful (e.g. loop diuretics), apart from

fluid administration alone: and N-acetylcysteine may at least do no harm.

26  

 

Chapter IV Discussion:

Acute kidney injury due to intravenous drug abuse may be reversible. Managing this case

would be based on the different diagnosis listed above. Firstly, treatment via controlling critical

measures which include maintaining adequate intravascular volume and mean arterial pressure,

discontinuing all nephrotoxic drugs, and eliminating exposure to any other nephrotoxins,

secondly by specific medications according to the diagnosis which either HAN, HIVAN or post-

infectious glomerulonephritis. Many medications can injure the kidneys therefore dosing

schedules (i.e. a once-daily dose is preferable than multiple daily doses) can help prevent acute

renal failure. A combination of ACE inhibitors and a loop diuretic ( e.g furosemide) will be

sufficient to control proteinurea and peripheral oedema. If the case is not responding to treatment

addition of thiazide diuretic (e.g., metolazone) will be required. Patients receiving this agent need

to be monitored for K+ level. The literatures mentioned variety of specific treatment for each

possible differential diagnosis discussed below as following:

Heroin-associated nephropathy (HAN)

Naloxone is an effective opioid antidote but it is not without harmful side effects.

Naloxone may be harmful for two reasons: (1) administration of naloxone with combined opioid

and sympathomimetic intoxication may provoke life threatening manifestations of

sympathomimetic toxicity by removing the protective opioid mediated CNS depressant effects

(Hung et., al 1998) (2) the risk of arrhythmia as arrhythmogenesis of naloxone is well

documented and the risk may increased in this case on the background of hyperkalaemia.

Therefore establishing the timing of ingestion of narcotics in relation to the time of presentation

is very crucial (McCann et al., 2002).

HIV-associated nephropathy (HIVAN)

Patients with biopsy-proven HIVAN treated with Antiretroviral therapy (ART) had better

renal survival compared with patients who did not receive ART. HIVAN should be considered as

an indication to initiate ART (Atta et al., 2006)

27  

 

Focal segmental glomerulosclerosis

Treatment is generally recommended for nephrotic patients (Korbet et al 1998) Current

protocols recommend treating with prednisone 1 mg/kg/d for 3 to 4 months. As with other

nephroses, angiotensin-converting enzyme (ACE) inhibitors reduce proteinuria and are

renoprotective (Savin et al., 1996).

Amyloidosis

The prognosis of patients with amyloidosis is poor and therapy with melphalan and

prednisone are recommended. In patients with AA amyloidosis, treatment should be focused on

resolving the chronic inflammatory state. Colchicine has been effective in treating amyloidosis,

in particular, in familiar Mediterranean fever (Livneh et al.,2001).

Treatment options of secondary (AA) amylodosis due to chronic parenteral drug use are

limited and the outcome for such patients on renal replacement was poor. Arresting the

progression of systemic amyloidosis depends on reducing inflammation and SAA precursor

protein production by treating the underlying condition. Spontaneous resolution and successful

treatment with colchicine of renal amyloidosis has been reported in intravenous drug users, which

supports the idea that removal of the inflammatory stimulus, usually chronic skin sepsis, can lead

to reversal of the disease (Connolly et al., 2006).

Postinfectious glomerulonephritis

However, in some adults the disease can be more chronic. Antibiotics and supportive

therapy are recommended. Increasingly other bacteria, such as staphylococci and gram-negative

rods, are implicated in causing postinfectious GN. The pathogenesis is presumed to also be

secondary to ICs. Alcoholics, diabetics, and intravenous drug users are most commonly affected

(Montseny et al., 1995).

Mesangiocapillary GN due to hepatitis C infection

Gold therapy has been associated most commonly with membranous nephropathy (MN);

however, MCNS and mesangial GN have been reported. Proteinuria has also been observed in

7% to 18% of patients treated with D-penicillamine. Proteinuria classically begins after 6 to 12

28  

 

months of therapy with these antirheumatic agents. The proteinuria is generally reversible but can

take over a year to abate after drug withdrawal (Schiff and Whelton, 2000). Cyclosporine causes

renal afferent arteriolar constriction, and biopsies reveal focal interstitial fibrosis, tubular atrophy,

and arteriolar hyalinosis. Toxicity is related to the doses used (≥5 mg/kg/d), age of patients (> 65

years of age) and degree of underlying kidney disease. It is recommended to follow renal

function closely, especially in the elderly, and to avoid combination therapy with NSAIDs.

Methotrexate rarely causes renal toxicity; however, it is excreted by the kidney and can

accumulatein patients with renal insufficiency (Cush et al., 1999).

Membranoproliferative GN

The secondary MPGN most commonly to be associated with hepatitis C infection in the

majority of cases (Johnson et al., 1993; Rennke, 1995). Monoclonal IgM, possessing rheumatoid

factor activity, is a cryoglobulin. The pathogenesis of the renal diseases is either related to

deposition of circulating ICs with attendant complement activation, or the monoclonal IgM may

additionally recognize endogenous glomerular proteins. The disease is a systemic vasculitis, with

the renal involvement typically demonstrating proteinuria, hematuria, renal insufficiency, and

hypertension. The efficacy of interferon-α and ribavirin for hepatitis C–related renal disease has

yet to be defined, but it is being used. Ribavirin should not be used with creatinine clearance less

than 50 mL/min. Long-term treatment with antiplatelet agents may slow progression of the

disease in adults (Zauner etal., 1994).

Nephrotic syndrome:

The goals of treatment are to relieve symptoms, prevent complications and delay

progressive kidney damage. Treatment of the causative disorder is necessary to control nephrotic

syndrome. Treatment may be required for life. Corticosteroid, immunosuppressive,

antihypertensive, and diuretic medications may help control symptoms. Antibiotics may be

needed to control infections. Angiotensin converting enzyme (ACE) inhibitors may significantly

reduce the degree of protein loss in the urine and are therefore frequently prescribed for treatment

of nephrotic syndrome.

29  

 

If hypertension occurs, it must be treated vigorously. Treatment of high blood cholesterol

and triglyceride levels is also recommended to reduce the risk of atherosclerosis. Dietary

limitation of cholesterol and saturated fats may be of little benefit, as the high levels which

accompany this condition seem to be the result of overproduction by the liver rather than from

excessive fat intake. Medications to reduce cholesterol and triglycerides may be recommended.

High-protein diets are of debatable value. In many patients, reducing the amount of protein in the

diet produces a decrease in urine protein. In most cases, a moderate-protein diet (1 gram of

protein per kilogram of body weight per day) is usually recommended. Sodium (salt) may be

restricted to help control swelling. Vitamin D may need to be replaced if nephrotic syndrome is

chronic and unresponsive to therapy. Blood thinners may be required to treat or prevent clot

formation (Mushnick, 2005)

Conclusion

In conclusion, the diagnosis of this patient likely is intra-renal acute kidney injury,

supported by the patient biochemical report which showed proteinuria, high serum creatinine.

Initially, the patient needs supportive treatment. Therefore the first line of treatment for this

patient is a symptomatic. In addition dietary treatment consisted of restricted dietary of salt,

protein and fluid.

The combination of a loop diuretic ( e.g furosemide) with thiazide diuretic ( e.g.,

metolazone) has additive effects and can be used to the patients who are not responding to loop

diuretics alone. If the K+ level decreased, supplementation of potassium or addition of potassium

sparing diuretics (amiloride or spironolactone) may be nessesary (Willcox and Tisher, 2005).

ACE inhibitor can be used to reduce proteinuria (longmore et al., 2004). Considering that ACE

inhibitor can cause hyperkalemia so need to monitor K+ level.

For long term treatment this patient need to admitted to rehabilitation centre to recover

from drug addiction.

30  

 

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