Does this patient have chronic interstitial nephritis (CIN)?

Chronic interstitial nephritis (Figure 1) comprises a large and diverse group of conditions characterized by:

Figure 1.

Chronic interstitial nephritis.

Urinary concentration defects (secondary to dysfunction of the kidney concentrating mechanism located in the medulla

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  • Occurs early in the course

  • Associated: nocturia, polyuria and nephrogenic diabetes insipidus (NDI) with complications of dehydration

Sodium wasting

  • Difficulties in reabsorbing salt, leading to a reversible fall in eGFR (estimated glomerular filtration rate) secondary to hypotension

  • Typical of chronic interstitial nephritis

Acidification defects

  • Diminished ability to produce/excrete ammonium

  • Non anion gap metabolic adidosis

Renal failure

  • Typically slow and insidious


  • Lack of aldosterone (secondary to hyporeninemic hypoaldosteronism) or tubular unresponsiveness

  • Worsens acidification defect secondary to decreased ammonium production


  • CLINICAL PEARL: usually < 1 gm/day

  • Low molecular weight proteins (immunoglobulins, beta 2 and alpha 1 microglobulin) are often present, NOT just albumin


  • Early in the course secondary to destruction of erythropoeitin (EPO) producing interstitial cells

Chronic interstitial nephritis and systemic disease
Sickle Cell Disease (SCD) (Please see chapter on sickle cell nephropathy)

Clinical manifestations

Urinary concentration defect

  • Often the 1st manifestation of kidney involvement

  • Seen even in patientss with sickle cell trait (HbAS)

  • Manifests as: increased risk of dehydration secondary to polyuria ± enuresis (especially in children), unresponsive to vasopressin

  • Due to medullary fibrosis and permanent destruction of collecting ducts

Acidification defect and hyperkalemia

  • Typically aldosterone independent secondary to medullary fibrosis

  • Worse with associated renal failure

Painless hematuria

  • Often gross hematuria, as a consequence of red blood cell (RBC) ‘sickling’, vascular obstruction and RBC extravasation

  • Usually UNILATERAL (LEFT >> RIGHT, 2nd to longer LEFT renal vein)

  • Occurs in both HbAS (Sickle trait) and HbSS (Sickle cell)

Cortical scarring

Renal papillary necrosis (RPN)

  • Infection may contribute to RPN

  • Due to focal infarction secondary to severe sickling

  • Persistent gross hematuria, oftern lateralizes

  • CLINICAL PEARL: must always consider medullary carcinoma in sickle cell patients with gross hematuria and requires radiologic imaging (renal ultrasound or contrasted computed tomography (CT) scan) ± cystoscopy

Renal medullary carcinoma

  • Rare though aggressive (often metastatic at the time of diagnosis)

  • CLINICAL PEARL: occurs more commonly in Sickle Cell Trait >> Sickle Cell Disease

Radiologic studiesRenal and bladder ultrasound

  • Helpful to evaluate for: stone, tumor, or RPN

  • Increased ECHOGENICITY= typical of SCD (may be seen in other hemoglobinopathies)

  • May see calcification of the medullary pyramids (non-specific finding)

  • Helical (non-contrasted) Abdominal CT

    May detect RPN earlier than ultrasound


  • Conservative

  • Adequate hydration (usually hypotonic fluids)

  • Sodium containing fluids may cause sodium retention and edema

  • Often have a blunted response to loop diuretics


Idiopathic, likely autoimmune, relapsing multisystemic disorder characterized by granulomatous inflammation

Clinical manifestations


  • Most common renal manifestation

  • Defined as: > 300 mg/24 hrs for men, > 250mg/24 hrs for women (or > 4mg/kg/day)

  • Risk factor for nephrolithiasis (calcium oxalate based stones)


  • Granulomas express 1 -α hydroxylase which allows for the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol)

  • Leads to: afferent renal vasoconstriction → decreased renal blood flow → renal failure

  • Found in 10-20% of patients with sarcoidosis

  • Associated: polyuria and sodium wasting

  • If chronic, leads to progressive tubulointerstitial inflammation ± calcium deposits, nephrocalcinosis ± calcium deposits, nephrocalcinosis ± CKD

  • Ultrasound and CT scan are sensitive for nephrocalcinosis

Granulomatous interstitial nephritis

  • CLINICAL PEARL: Noncaseating granulomas = classic renal lesion, though found in only a small proportion of patients

  • Renal biopsy – granulomatous inflammatory infiltrate is confined to the cortex (versus drug-induced interstitial nephritis, predilection for corticomedullary junction (Figure 2)

  • Need to consider other potential etiologies: tuberculosis (TB), brucellosis, fungal infection, foreign-body reaction (secondary to drugs: nonsteroidal antiinflammatory agents (NSAIDs), allopurinol, anticonvulsants and diuretics), cholesterol emboli, lymphoma, Wegener granulomatosis or Idiopathic

Figure 2.

Granulomatous interstitial nephritis.

Renal tubular dysfunction

  • Proximal RTA ± Fanconi’s Syndrome or Distal RTA

  • Mild urinary concentration defects

  • Nephrogenic Diabetes Insipidus

  • Moderate to Severe Chronic Kidney Disease (serum creatinine average 2.98 – 4.79 mg/dL)

  • Proteinuria: typically <1 gm/day


-Conservative measures:adequate hydration, avoidance of excess dietary calcium and vitamin D, avoidance of ultraviolet (UV) light exposure and dietary oxalate restriction

-Thiazides (for hypercalciuria) should be AVOIDED, may predispose to hypercalcemia

-Corticosteroids (Prednisone 0.5-1mg/kg/day) are typically used for granulomatous interstitial nephritis

-Corticosteroids are the cornerstone of therapy for hypercalcemia and hypercalciuria

-Inhibit macrophage 1 -α hydroxylase and blunt the effects of calcitriol on intestinal calcium absorption and bone resorption

-Typical dose =Prednisone 20-40mg/day

-May develop incomplete recovery of renal function 2nd to Nephrosclerosis

Sjögren's Syndrome

-Chronic systemic autoimmune disease characterized by: lymphocytic infiltration of exocrine glands (lacrimal and salivary)

-Renal involvement occurs in 18.4-67% pts with primary Sjögren’s syndrome

Common laboratory features

(+) ANA (85%), Anti-Ro >> Anti-La antibodies (80% versus 40%), (+) Rheumatoid factor (82%) and increased ESR

Clinical manifestations

Tubular proteinuria

  • ~ 1 gm/day

  • Low molecular weight proteins (β2 microglobulin [β2M] and retinol binding protein [RBP])

Interstitial Nephritis

  • Occurs in ~ 25% patients and often an EARLY manifestation (average of 2.2 years after disease presentation)

  • CLINICAL PEARL: Most cases of interstitial nephritis are asymptomatic and subclinical

  • There are no serologic differences between those with and without renal disease

  • Chronic tubulointerstitial nephritis (TIN) is more common than acute TIN

  • Renal Biopsy: small lymphocytes, plasma cells and monocytes in the interstitium with tubular atrophy and fibrosis

    Focal or diffuse lymphocytic infiltrates in the renal tubules similar to infiltrates in the salivary glands

    Plasmacytoid lymphocytic infiltration = important predictive factor for activity of disease

  • Unusual to develop ESRD

Hyposthenuria and Nephrogenic Diabetes Insipidus (NDI)

  • Urine specific gravity < 1.010

  • Urine osmolality < 285 mOsm/kg

Type 1 (Distal) Renal Tubular Acidosis (RTA)

  • CLINICAL PEARL: May be present in up to 40% of patient with Sjögren’s syndrome, but rarely clinically apparent

    Thought to be due to defect in H+-ATPase

  • Mainly found if extensive histologic and immunologic disease

    ~ 50% have hypokalemia

    Urine pH > 5.5 and Urine K+ excretion is increased (> 20 mmol/L on a spot urine sample with hypokalemia)

  • Often associated hypergammaglobulinemia and increased IgG levels (may have a pathologic role in the tubular dysfunction)

  • May have associated:
    Nephrocalcinosis and Nephrolithiasis

  • Hypokalemic periodic paralysis may be a rare manifestation

  • Corticosteroids (Prednisone 0.5-1.0 mg/kg/day) are often used in conjunction with potassium repletion, though the RTA may not respond

Type 2 (Proximal) RTA and Fanconi Syndrome

  • Much LESS common than distal RTA

Glomerular disease is rare and often associated with mixed cryoglobulinemia

  • Usually have a LOW C4


  • Early usage of corticosteroids (Prednisone 0.5-1.0 mg/kg/day) with tapering doses though the efficacy of long-term usage is unknown

  • Cyclophosphamide has been used in patients with severe TIN (should be considered in consultation with Nephrology and Rheumatology)

Chronic interstitial nephritis and medications
Analgesic Nephropathy
  • Formerly resopnsible for 1-3% ESRD cases

  • Typcially seen after DAILY ingestion of analgesic mixtures, containing phenacetin and aspirin or acetaminophen (paracetamol), often mixed with codeine or caffeine

  • CLINICAL PEARL: Usually seen post prolonged and excessive consumption

    Minimum = 1 gm daily x 6-8 yrs

    Requires combination of medications

    ? Removal of phenacetin from the US and European markets has led to a reduced number of patients with analgesic nephropathy

  • Acetaminophen

    Primary metabolite of phenacetin

    Multiple studies have suggested that acetaminophen is nephrotoxic but the question remains imcompletely resolved

    Initially suggested in a case-control study (Perneeger et al, NEJM, 1994)

    Association between the cummulative intake (# pills ingested per lifetime) and relative risk

    Nurses Health Studay (Archives of Internal Medicine 1994)

    Increased acetaminophen use (> 3000 gm total) had an associated decrease of eGFR

    There is suggestive but NOT definitive evidence that patients that use chronic DAILY acetaminophen may develop nephrotoxicity

  • Acetylsalicylic acid (Aspirin)

    Most studies suggest aspirin usage alone does NOT result in nephrotoxicity

    May potentiate acetaminophen nephrotoxicity if used in combination


    AKI from decreased synthesis of vasodilatory protaglandins which decrease renal blood flow

    May cause MULTIPLE renal effects: sodium and water retention →edema, HTN, Hyperkalemia, Interstitial Nephritis, Nephrotic Syndrome secondary to Minimal Change Disease (or Membranous GN) and AKI

    Role of NSAIDs in the development of CKD Remains Uncertain

    Physicians Health Study (Rexrode et al, JAMA, 2001)

    11,000 males followed over a 14 year period

    Increased relative risk of an elevated serum creatinine (> 1.5 mg/dL) was NOT associated with exposure to: acetaminophen, aspirin or NSAIDs, but the study was limited by: retrospective analysis, single creatinine measurement and questionnaire based

    High Cumulative NSAID exposure (>= 90th percentile) is associated with an increased risk of rapid CKD progression in the community based elderly (mean age = 76 yrs old) (Gooch et al, The American Journal of Medicine, 2007)

    26% reached primary outcome of decrease (change) in eGFR >= 15 ml/min/1.73m2

    Nephrotoxicity may be dose-dependent (takes >= 5 years to develop)

    Renal damage is most prominent in the medulla

    Early changes: damage to the vascular endothelial cells

    Late changes: focal segmental glomerulosclerosis (FSGS)+ interstitial fibrosis

Clinical manifestion

Patients typically develop renal papillary necrosis or chronic interstitial nephritis

  • Reduced concentrating ability (polyuria)

  • Sterile pyuria

  • Renal colic

  • Microscopic or gross hematuria

  • Mild decrease in eGFR or insidious develpment of renal failure 2nd to chronic interstitial nephritis

NSAID induced Interstitial Nephritis and Nephropathy
  • Manifests: days to months post exposure (average 5.4 months)

Variable clinical features

  • CLINICAL PEARL: fever, drug rash, eosinophilia and eosinophiluria is USUALLY absent

  • Edema is usually present

  • Urinalysis: may see microscopic henaturia and renal tubular epithelial casts

  • Proteinuria is typically in the nephrotic range

    After discontinuation, proteinuria usually resolves, but may take up to a year

    Steroids (as outlined in the AIN section), can be considered, but the data are controversial and retrospective

Papillary Necrosis
  • May occur with CHRONIC usage (daily usage over years)

  • Mechanism is NOT well understood

  • Associated CHRONIC interstitial nephritis on renal biopsy

    Affects the cortical (outer) regions


Renal Ultrasound

  • Decreased renal size

  • Irregular “bumpy” contours and blunted calyces

  • Papillary calcifications

Non-contrast Abdominal CT Scan

  • Defined criteria (as adapted from Debroe ME, New England Journal of Medicine, 338:447, 1998)

  • Similar characteristics as renal ultrasound i.e. diminshed size, bumpy contours and papillary calcifications

  • Best sensitivity and specificity

Lithium (Li3+) and Nephrotoxicity
  • Freely filtered and ~ 80% reabsorbed in the proximal tubule

Clinical manifestation

  • Multiple nephrotoxic effects

  • Nephrogenic Diabetes Insipidus (NDI)

    Occurs in up to 40% of patients

    Most common drug induced effect and may be seen EARLY

    Presumed secondary to downregulation of AQP-2 water channel expression (on the apical/luminal side of the principal cell)

    Amiloride may attenuate NDI by blocking tubular reabsorption of Li3+ (blocks epithelial sodium channel, ENaC)

  • Chronic Tubulointerstitial nephritis

    Characterized by insidious renal failure and progression to ESRD

    CLINICAL PEARL: Most commonly seen post long-term usage (AVERAGE = > 15 years)

    Serum creatinine > 2.5 mg/dL is the most predictive of progression to ESRD

    Occurs despite withdrawal of Li3+ therapy

    ~ 60% have <= 1 gm proteinuria/day

    ~ 25% have nephrotic range proteinuria

    Often have associated FSGS

    Associated HTN in ~ 33%

    Does not require episodes of Li3+ intoxication

Renal biopsy

  • Interstial fibrosis and tubular atrophy out of proportion to the degree of glomerulosclerosis and vascular changes

  • Cortical and Medullary cysts (in areas of atrophy and fibrosis) = specific and highly characteristic finding


  • Withdrawal of Li3+ if progressive renal failure (and OTHER potential causes for renal failure are ruled out)

    ** This MUST be done in conjunction with Psychiatry/Psychology consultation to assist with provision of other adjunctive medications or modalities

  • If Li3+ therapy continues, CLOSE monitoring of: renal function and electrolytes (basic metabolic profile or renal panel), thirst, urine volumes and urine specific gravity (monitoring of NDI)

  • Development of NDI may be magnified during hospitalization or development of acute systemi illness (ESPECIALLY if access to free water is limited)

Phosphate Nephropathy
  • 1st described in 2003 in a case report in the New England Journal of Medicine (Desmeules et al)

  • Relatively rare presentation, but MUST be considered in the appropriate circumstances (elderly, recent colonoscopy prep)

    It is an underrecognized cause of BOTH AKI and CKD, though the FDA issued an ALERT May 2006 in which it detailed cases of acute phosphate nephropathy associated with Oral Sodium Phosphate (OSP)

    December 2008, The FDA issued a black box warning eventually leading to a voluntary recall of their OSP preparartions and ultimately manufacturers ceased distrivution

  • 3 agents: Fleet’s Phospho-soda© oral solution, OSP tablets (Visicol© and Osmo-Prep©), and Fleet’s Enema©

  • The mechanism of OSP induced AKI is likely multifactorial

Clinical presentation

Two Forms:

  • Acute Presentation:

    Shortly after exposure to OSP preparations

    Often baseline renal function is normal

    ELEVATED serum phosphorus (may be confused with any cause of AKI)

    Low to normal serum calcium

  • Subacute Presentation:

    Incidentally discovered, weeks to months post exposure

    Mild, non-specific symptoms

    Serum calcium and phosphorus are normal

    Often associated conditions: pre-existing CKD, Hyperparathyroidism, HTN, DM, CHF, Use of ACE inhibitors, ARBs, Diuretics and NSAIDs, Advanced age or Volume depletion

Urine sediment:

  • bland

  • ± Intermittent hematuria or pyuria

  • Low grade proteinuria (< 1 gm/day)

  • CLINICAL PEARL: given the paucity of clinical findings, often these patients do NOT undergo renal biopsy and the only important clinical information is the history of PRIOR exposure to phosphate products

  • Largest Observational Study (Hurst et al, Journal of the American Society of Nephrology, 2007)

    Identified 83 patients (out of 6342 patients total) with an elevated serum creatinine after exposure to OSP, with an exposure rate = 1.3%

Renal biopsy:

  • Intra-tubular nephrocalcinosis with extensive tubulointerstitial deposition of calcium phosphate (non-polarized deposits with (+) von Kossa staining)


  • Many cases in the subacute exposure group are left with residual CKD and there have been cases of ESRD

    Markowitz et al, Journal of the American Society of Nephrology, 2005: 4/21 patients in their cohort developed ESRD

  • CLINICAL PEARL: None of the patients serum creatinine returned to baseline


  • Awareness is the MOST IMPORTANT factor

  • Adequate hydration before, during and after colonscopy has been suggested (MINIMUM of 72 ounces of fluid intake)

  • AVOIDANCE of OSP in elderly patients and those with the above listed associated conditions

  • Consideration of avoidance of: Diuretics, NSAIDs, ACE inhibitors and ARBs during the colonoscopic prep (NOT evidence based)

  • Dose reduction from 90ml to 75 ml of OSP (newer formulations with reduced phosphate dosage)

Acyclic Nucleoside Phosphonates and Tubular Toxicity
  • Direct tubular toxicity is the major mechanism

  • Mechanisms of Toxicity:

    Effects on the human organic anion transporter 1 (hOAT1)

    Allows influx of these medications (20-30% is ACTIVELY transported into renal proximal tubule cells)

    Efflux occurs via multidrug resistance-associated protein (MRP)

  • Tenofovir (Nucleoside reverse Transcriptase Inhibitor, NtRTI

    Eliminated unchanged in the urine by glomerular filtration and proximal tubular secretion

    Structurally similar to acyclic nucleotides: adefovir and cidofovir

    Impair mitochondrial replication by inhibition of DNA polymerase-γ

Clinical manifestations

  • Drug associated Fanconi Syndrome

    May have proximal tubular dysfunctionwith preserved renal function

    May be partial or complete

    May have β2- microglobulinuria

  • Nephrotoxicity

    Persistently elevated serum creatinine and decline in eGFR

    Episodes of AKI from toxic ATN

    Usually non-oliguric

    Typically preceded or accompanied by tubular damage

    Often in association with OTHER nephrotoxins (NSAIDs or Aminoglycosides)

    Majority of patients received concomitant protease inhibitors (Ritonavir boosted protease inhibition, Lopinavir and Abacavir)

    Likely leads to higher systemic and intracellular levels of TenofovirNDI has been reported in a few cases

    Predictors of nephrotoxicity: low body weight, advanced HIV disease, older age, preexisting renal impairment and ABCC2 gene polymorphism

    Herlitz et al, Kidney International, 2010:

    Reported on renal biopsy data in 13 cases of Tenofovir (TDF) nephrotoxocity

    Mean age at biopsy = 51.1 ± 9.6 years

    10/13 patients had undetectable viral load with mean CD4 count of 339 ± 270 cells/ml

    Duration of TDF therapy at time of biopsy ranged from 3 weeks to 8 years (mean = 19.6 months and median = 8 months)

    Mean serum creatinine at time of biopsy =5.7 ± 4.0 mg/dL (range 1-13 mg/dL)

    Mean proteinuria (24 hour urine) = 1.6 ± 0.3 g/day (All were sub-nephrotic)

    Normoglycemic glycosuria in 7/13 (consistent with Proximal Tubular Dysfunction)

    Renal biopsy:

    Proximal tubular injury (mild and localized to diffuse and severe [11/13])

    Varying degrees of chronic tubulointerstitial scarring

    10/13 cases features of acute tubular injury predominated

    Light microscopy: prominent eosinophilic intracytoplasmic inclusions within the proximal tubular epithelium (represent giant mitochondria)

    Course post discontinuation:

    3 patients required dialysis for ~ 1 month

    Complete recovery 6/13 patients (mean follow-up 11.5 ± 13.6 months)

    Partial recovery 5/13 patients (renal function did not return to baseline)

  • NDI has been reported in rare cases


  • Patients should have frequent monitoring (biannual) of: serum creatinine, potassium, phosphate, bicarbonate, serum uric acid and urinalysis for glucose and protein

    Especially if co-morbid conditions: HTN, DM or concomitant use of nephrotoxins

  • Drug discontinuation rates are low, unless progressive decline in renal function

  • Probencid has been suggested as an inhibitor of hOAT1 (which may REDUCE proximal tubular entry of TDF)

  • CLINICAL PEARL: Tenofovir should be adjusted if eGFR < 60ml/min/1.73m2

Adefovir Dipivoxil

Clinical manifestations

  • Glucosuria = EARLIEST feature of tubular toxicity

  • Fanconi Syndrome

  • Progressive renal impairment

    Often dose related

    Direct mitochondrial toxicity (affects synthesis of Cytochrome C oxidase)


  • Adequate hydration

  • Probenecid (given before and after usage) may limit toxicit

  • Caution if: eGFR < 60ml/min/1.73m2 and usually requires dosage adjustment

Mesalamine and Aminosalicylate Compounds

Clinical manifestations

  • AIN and Glomerulonephritis are uncommon (likely 2nd to poor recognition)

  • CIN is the most common presentation with progressive renal failure

    May take months to develop

    CLINICAL PEARL: Fever, rash, arthralgia and eosinophilia are uncommon

    Asymptomatic azotemia, microscopic hematuria and proteinuria (non-nephrotic) are common

  • Diagnosis should be made early and often requires a renal biopsy

    Early diagnosis (< 10 months of total drug usage), lesion regresses in up to 85% pts

    Delayed diagnosis (> 18 months), despite drug withdrawal, recovery ONLY in 1/3 of pts


  • Value of added immunosuppression is unknown and improvement may take weeks to 1 year

  • Suggested monitoring includes:

    Monthly for the 1st 3 months, then quarterly, then annually after the 1st year

    Any sustained increase in serum creatinine should result in withdrawal of Mesalamine

    If renal function does NOT recover to baseline after withdrawal, then renal biopsy is indicated

Chronic interstitial nephritis and medications
Urate Nephropathy
  • Chronic toxicity from accumulation of uric acid is controversial

  • Mechanism: thought to be inflammatory secondaryto deposition of urate crystals in the medullary interstitium andparenchyma –> progressive tubulointerstitial injury

  • There is an association between hyperuricemia and CKD

    Though there is a putative pathogenetic role of uric acid, other factors may be contributory (Age and HTN)

    Hyperuricemia accompanies CKD secondary to a reduction in urate excretion

    Bellomo et al (AJKD, 2010): evaluated the association between hyperuricemia and GFR in aprospective cohort of healthy normotensive adult blood donors

    Higher serum uric acid was associated with worsening kidney function

    Obermayr et al (JASN, 2008): prospectively followed 21,475 healthy volunteers for 7 years andexamined the association between uric acid levels and incident kidneydisease (eGFR < 60 ml/min/1.73m2)

    Elevated serum uric acid (7-8.8 mg/dL) was associated with nearly doubled risk for incident kidney disease

    Elevated serum uric acid (>= 9 mg/dL) was associated with nearly tripled risk of incident kidney disease

    Hyperuricemia precedes the reduction in eGFR

    Often associated with: HTN Mild proteinuria (< 1gm/day) and a Bland urinary sediment

  • Murray and Goldberg (Annals of Internal Medicine 1975), defined an elevation in serum urate concentration out of proportion to the degree of renal failure as follows:

    > 9 mg/dL if serum creatinine < = 1.5 mg/dL

    > 10 mg/dL if serum creatinine between 1.5-2.0 mg/dL

    > 12 mg/dL if serum creatinine between 2.1 -3.0 mg/dL

  • Though the association between acute kidney injury (AKI) and elevated serum uric acid levels in the setting of tumor lysis syndrome is NOT disputed, whether chronic elevations of serum uric acid → urate nephropathy remains controversial

    Acute urate nephropathy may be accompanied by:

    Oliguria → anuria

    Urinary uric acid/creatinine ratio > 1

1. Treatment:

  • Allopurinol (or Febuxostat) may be used to lower serum uric acid but its role in slowing progressive CKD remains controversial

  • Allopurinol Trials:

    Siu et al (AJKD 2006): Prospective, randomized, controlled trial of 54 hyperuricemic patients (serum uric acid 9.75-9.92 mg/dL), Stages 3-4 CKD and proteinuria (> 0.5 gm/day) treated with Allopurinol 100-300 mg/day versus usual therapy

    Serum uric acid levels decreased from 9.8 mg/dL → 5.9 mg/dL in the Allopurinol Treated Group with 16% reaching the endpoints of > 40% deterioration of creatinine versus 46% in the Usual Therapy Group

    Goicoechea et al (ClinJournal of the American Society of Nephrology 2010): Prospective,randomized trial of 113 participants with eGFR < 60 ml/min/1.73m2 treated with Allopurinol 100 mg/day or usual therapy x 2 years.

    Mean serum uric acid was 7.9 ± 2.1 mg/dL (Allopurinol Treated Group) versus 7.3 ± 1.6 mg/dL (Usual Treated Group)

    Serum uric acid decreased with Allopurinol (7.8→ 6 mg/dL)

    The Allopurinol Treated Group had an INCREASE in eGFR by 1.3 ml/min/1.73m2 versus the Usual Treated Group (control) [DECREASE in eGFR by (-) 3.3 ml/min/1.73m2]

    Preliminary results showed that Allopurinol treatment may:

    Reduce cardiovascular events (by reduction in inflammatory markers (i.e hs-CRP)

    Reduce hospitalizations

    The evidence to treat ALL asymptomatic patients with hyperuricemia remains controversial

Hypokalemic Nephropathy

  • Few reports on the natural history of hypokalemic nephropathy

  • Most associated with: primary hyperaldosteronism, drugs which deplete potassium (laxatives and diuretics) or malnutrition (anorexia nervosa)

    Frequently have associated neurosis

    Women >> Men

1. Clinical Manifestations:

  • Low to normal BP

  • Polyuria 2nd to NDI

    Typically seen with chronic K+ depletion (< 3.0 mEq/L)

  • Minimal proteinuria

  • Majority have reduced eGFR and azotemia

    Severity of renal impairment correlated with duration and degree of potassium depletion

    Associated: hyponatremia, hypochloremia and metabolic alkalosis

  • Recurrent edema

  • Plasma renin acitivity and serum aldosterone concentration are variable

    Frequently pts have evidence of 2nd hyperaldosteronism

2. Imaging:

  • Kidney size within the normal range

3. Renal Biopsy:

  • Renal biopsy: tubular atrophy, thickening of the peritubular basement membranes and interstitial fibrosis

    juxtaglomerular hyperplasia

  • Patients with primary hyperaldosteronism show similar renal biopsy findings

  • Increased prevalence of renal medullary cysts on cross-sectional studies

    Long duration of HTN and lower potasium levels correlate with the extent of cystic disease

    The severity of hypokalemia may be a MAJOR determinant of cyst formation

4. Treatment:

  • Cystic disease does NOT progress after medical or surgical treatment of primary hyperaldosteronism

Chronic Interstitial Nephritis and Immune-Mediated Disease

Chronic interstitial nephritis and immune-mediated disease
Immune-related Potassium-losing Interstitial Nephritis (IRPLIN)

1. Clinical Manifestations:

  • Usually have associated autoimmune disease

  • Typically female

  • No associated RTA, nephrocalcinosis or Metabolic Bone Disease

2. Renal Biopsy:

  • Features of chronic interstitial nephritis with lymphocytic infiltrate

3. Treatment:

  • Treat the associated condition(s) and replete K+ >= 4.0 mEq/L (and associated electrolyte abnormailties)

Idiopathic Hypocomplementemic Immune-Complex-Mediated Tubulointerstitial Nephritis

  • Few cases described in the literature

1. Clinical Presentation:

  • Seen in older males

  • Typically presents with:

    Advanced renal failure

    Severe hypocomplementemia

    Eosinophila and eosinophiluria


    Absence of Sjögren’s or SLE

    May have low titer ANA (1:80)

    Urinalysis is bland (no cells or casts) without proteinuria

  • May evolve into Marginal Zone B-cell Lymphoma

2. Renal Biopsy:

  • Plasma cell interstitial infiltrate

  • Electron dense deposits in the tubular basement membrane

    Stain (+) for IgG, Kappa and Lambda

    Variable staining for C3 and C1q

3. Treatment:

  • Prednisone +/- Cyclophosphamide

  • No long-term prospective studies as reports are limited to case reports and series

Tubulointerstitial Nephritis with IgG4-related Systemic Disease

1. Clinical Presentation:

  • Middle-age to elderly men (> age 50 yrs)

  • Sialdenitis

  • Lymphadenopathy

  • Hypocomplementemia

  • Serum total IgG and IgG4 levels are increased

  • ANA (+)

  • Autoimmune pancreatitis

    Diffuse swelling of the pancreas

    Associated: sclerosing cholangitis, retroperitoneal fibrosis and sclerosisng sialdenitis

    Increased levels of λ-globulin (IgG4)

    Steroid responsive

2. Renal Biopsy:

  • Dense lymphoplasmacytic infiltration with fibrosis

  • Plasma cells with immunoreactivity for IgG4

  • Found in extrarenal organs: salivary glands and pancreas

3. Other Associations:

  • May be seen in Mikulicz’s Disease and Sjögren’s Syndrome with IgG4-positive plasma cell infiltration

  • Case reports of Chronic Tubulointerstitial Nephritis with Multiple Renal Nodules and Pancreatic Insufficiency (2nd to Autoimmune Pancreatitis)

    Increased levels of IgG4

4. Treatment:

  • Corticosteroids: Prednisone 30-40mg/day with gradual wean, but may recur, requiring maintenance dose of 5-10 mg/day

Chronic interstitial nephritis and toxins
Divalent Cations (Heavy Metals) and Nephropathy
  • 38% of adults use complementary and alternative forms of medicine, typically over-the-counter products (2007 National Health Interview Survey)

  • Potential for adulteration of these products with heavy metals/divalent cations (Lead, Cadmium, Arsenic and Mercury)

  • Saper et al, JAMA, 2008: ~ 21% of Ayurvedic medicines used in the practice of ‘rasa shastra’, contained detectable levels of: lead (most common), mercury and arsenic

Cadmium Nephrotoxicity (Cd)

  • Typically seen via industrial or environmental exposure (cigarrette smoke or food based)

  • By-product of zinc refining

  • Most significant source: nickel cadmium batteries

  • Long biologic half-life, ~ 30 years

  • Blood cadmium level (whole blood) can be used to monitor BOTH recent and remote exposure

1. Clinical Presentation

  • Nasorespiratory illnesses: anosmia, rhinitis, emphysema, ? cancer

  • Disturbances in calcium metabolism

  • Osteomalacia

    ‘itai-itai-byo’ (‘ouch-ouch’ disease), crippling and painful osteomalacia endemic to the Jinzu River Basin

    Increased in middle aged postmenopausal women

    Diffuse pain, myalgias and ‘ducklike’ gait

    Often have associated Fanconi’s Syndrome

  • Nephrolithiasis 2nd to hypercalciuria

  • Renal Tubular Dysfunction


    Mixed type: high and low molecular weight proteins

    α 1-microglobulin is used as a marker of tubular proteinuria

    Metallothionein : Produced in response to cadmium exposure and excreted in increased quantities when the body burden of cadmium exceeds a threshold (urinary cadmium level > 3.1 μg/gm creatinine)

  • Proteinuria may be irreversible (even several years post exposure)

  • Fanconi’s Syndrome

  • Type 1 (Distal) RTA

    Tubular dysfunction may be irreversible

  • GFR impairment

    Worsens the age-related decline in GFR

  • Hypertension

    Association with HTN is not conclusive

    May be 2nd to impaired pressure natriuresis response

2. Treatment

  • Careful occupational history to minimize exposure

  • NO chelation therapy is available

Lead Nephropathy

  • Lead usage can be traced back to biblical times

  • Lead was eliminated from house paint in 1978, and from gasoline in 1996

  • Still a potential source of contamination in developing countries

  • Moonshine whiskey: potential source of lead contamination in the US

    Often distilled in car radiators

    Parts of the stills soldered together with lead based solder

  • Short half-life in whole blood ~ 35 days

1. Diagnosis:

  • Occupational history is very important

  • CLINICAL PEARL: use of blood lead measurements (serum) only useful for recent exposure and NOT helpful in chronic exposure

    Rapidly taken up by RBCs and bone

    Lead in whole blood is bound to δ aminolevulinic acid dehratase (ALAD)

    Polymorphisms of ALAD-2 may modify lead binding and reduce the propensity for lead intoxication

  • Lead accumulates in bone

    Half-life in cortical bone (mid-tibia) ~ 27 yrs versus cancellous bone (patella and calcaneus) ~ 15 yrs

    Radiographic fluorescence techniques provide a noninvasive measurement of lead within bone but typically available only in research facilities

  • Standard measurement

    EDTA lead mobilization test: collect urine for 24hrs after intravenous or intramuscular EDTA (2gm in divided doses)

    If SCr > 1.5mg/dL, urine should be collected for 72 hrs

    POSITIVE TEST: if subject excretes > 600 μg of lead chelate

    Levels of 80-600 μg may be abnormal (Lin et al, NEJM, 2003), though most recently, levels > 20 μg are consistent with excess tissue burden of lead

  • CLINICAL PEARL: Diagnosisof lead nephropathy should be considered in pts with an appropriateoccupational history, in combination with: HTN, slowly progressive CKDand tophaceous gout

    Studies suggest measurement of a blood lead level, if > 10 μg/dL, referral to a specialist in occupational and environmental medicine

2. Clinical Presentation:

  • Acute intoxication

    More common in children

    Abdominal pain, Neurologic symptoms and Pallor (microcytic anemia)

    Associated Fanconi’s syndrome

    Renal biopsy: acid-fast granular intranuclear inclusions (myeloid bodies) in the proximal tubular cells

  • Chronic intoxication

    Related to occupational exposure, remote childhood exposure or moonshine whiskey ingestion

    Both remote childhood exposure and moonshine whiskey ingestion may be associated with Saturnine Gout (often tophaceous) associated with HTN and Renal Failure

  • Renal Failure

    Chronic high level exposure (> 70-80 μg/dL) may be a risk factor for CKD (WHO group)

    May exaccerbate other forms of CKD including Diabetes

    10 fold increase in blood lead may be associated with a reduction in GFR ~ 10-13 ml/min (Payton, American Journal of Epidemiology, 1994)

  • Tubulointerstitial disease

    Polyuria and impaired urinary concentration

    Salt wasting

    Secondary to hyporenin hypoaldosteronism

  • RTA

    Proximal >> Distal

    Proximal RTA is more common in children than adults

    Usually seen with acute intoxication

  • Sterile pyuria

  • Hypertension

    Positive correlation between blood lead levels and HTN

  • Hyperuricemia

    2nd to decreased urate excretion

    Predispoistion to gout

    Often tophaceous

    Termed ‘saturnine ‘

3. Imaging:

  • Kidneys may be small and contracted (granular appearance)

4. Renal biopsy:

  • focal tubular atrophy, interstitial fibrosis with minimal cellular infiltrate

  • non-immunologically mediated interstitial nephritis

5. Treatment

  • Acute intoxication, typically treated with calcium EDTA

    Suggested strategy: <=50 mg/kg/day (1 gm calcium EDTA in 250 ml 0.9 saline intravenously over2-3 hrs @ a rate of 20 mg/min) for 5-7 consecutive days

    Large doses, rapid adminisration or co-morbidities may be associated with ATN

    Zinc (and other trace metals) excretion has been associated with the use of calcium EDTA, ? clinical significance

  • Should be treated by an experienced occupational medicine clinician with familiarity of cases of lead toxicity and usage of chelation agents

  • Chronic intoxication

    The role of chronic lead nephropathy from low level exposure in the development of CKD remains controversial and inconsistent over studies (Evans and Elinder, KI, 2010)

    Often associated with co-morbid factors: Diabetes mellitus, HTN and underlying CKD

    A detailed occupational history must be performed and all sources of potential lead exposure must be eliminated

    Chelation therapy may stabilize or slow the progression of lead induced CKD

    May have IMPORTANT public health benefits

    Multipledifferent calcium EDTA protocols have been described in the literatureand the decision to treat cases of chonic lead nephropathy must be individualized and performed in consultation with an experienced occupational medicine specialist

Aristolochic Acid Nephropathy (AAN, formerly known as Chinese Herb Nephropathy)

  • 1 out of every 3 people in the US will use at least 1 form of alternate or complementary medication

  • Often pts do NOT inform their physician about usage

  • Typical users: middle-class white women, age 20-49 yrs of age

1. Backround:

  • Initially described in young Belgian women who used herbs as a slimming agent

  • One of the prescribed herbs imported from China, Stephania terandra (‘Hang Fang-ji’) was inadvertently substituted by Aristolochia fangchi (‘Guang Fang-ji’)

  • There are MULTIPLE botanicals known to contain various species of Aristolochic acid

  • Aristolochic acid is a nephrotoxin and carcinogen plant alkaloid

2. Clinical Presentation:

  • Female predominance

  • Insidious onset

  • Anemia out of proportion to the degree of renal disease

  • Fanconi syndrome (2nd to proximal tubular dysfunction)

  • Little edema on examination

  • HTN is absent

  • Extrarenal manifestations: aortic insufficiency

  • Urinalysis

    CLINICAL PEARL: minimal proteinuria

    Varying degrees of glucosuria

    Increased urinary excretion of low molecular weight proteins

    Increased urinary low molecular weight protein/albumin ratio

3. Imaging:

  • Renal Ultrasound: Small kidneys ± asymmetric with irregular outlines

4. Renal Biopsy:

  • Extensive interstitial fibrosis with tubular atrophy (cortex)

  • ± Hypocellular interstitial infiltrates

5. Prognosis:

  • Rapid progression to ESRD (6 months — 2 years)

  • CLINICAL PEARL: High prevalence of Urothelial Malignancies (40-50%) of:

    Upper urinary tract (multifocal high-grade transitional cell carcinoma) and bladder

    ** Most commonly detected in pts with ESRD

    Correlates with cumulative ingested dose

6. Therapy:

  • Supportive therapy

  • Steroids (if interstitial infiltrates) may slow progression to renal failure

  • Consideration of prophylactic BILATERAL nephrectomy and ureters in pts treated by dialysis or renal transplantation

Balkan Endemic Nephropathy (BEN)
  • Affects people living along the tributaries of the Danube River in Bosnia, Herzegovina, Bulgaria, Croatia, Romania and Serbia

  • Some villages in the endemic regions that are not affected are separated from affected areas by a few kilometers

    Not all households within the same village involved

  • Environmental factors are more important than genetic factors

  • Development related to total time (>= 20 yrs) spent in the area

1. Clinical Presentations:

  • Typically originate from an endemic village

    (+) Family history (specific marker on chromosome 3)

  • Mild proteinuria (< 1 gm/24 hrs)

  • Low urinary specific gravity (± < 1.010)

  • Anemia

  • Azotemia

  • Slowly progressive tubulointerstitial nephropathy

  • High prevalence of urothelial tumors of the upper urinary tract and bladder

    11.2 fold higher risk versus nonendemic areas

2. Imaging:

  • Symmetrically shrunken kidneys with smooth outline

3. Renal Biopsy:

  • Progressive tubular atrophy and sclerosis

  • Hypocellular diffuse cortical interstitial fibrosis

4. Pathogenesis:

  • Similiarities between Aristolochic Acid Nephropathy and Balkan Endemic Nephropathy

  • Main difference: rates of progression to ESRD

    AAN progresses rapidly, 6 months to 2 yrs

    BEN progresses slowly, > 20-30 yrs

  • Postulated environmental factor:

    Aristolochia clematitis ( common weed found in the fields) contaminating wheat eventually made into flour

    Ochratoxin (mycotoxin) detected in food items in endemic areas

    Coals generating water-soluble hydrocarbons contaminating the drinking water

5. Treatment:

  • Supportive, though screening of adults with risk factors in endemic areas is cost-effective

  • Surveillance for urothelial tumors is mandatory

  • Recurrence of BEN in renal allografts has NOT been documented

Chronic interstitial nephritis and miscellaneous conditions
Renal Papillary Necrosis (RPN)
  • Not a distinct disease process, but a clinico-pathologic syndrome

  • May be associated with ischemic necrosis 2nd to vascular impairement and the associated hypertonic environment

  • Associated conditions can be remembered by the Mnemonic = POSTCARD


    E coli = most frequent organism

    Urinary Tract Obstruction

    Sickle Cell Disease (BOTH trait and disease)



    Analgesic Nephropathy

    Radiation Nephritis

    Diabetes mellitus

    Most frequent cause of RPN

    May be bilateral

1. Clinical Presentation:

  • Often MULTIFACTORIAL cause and co-existence of conditions

  • Associated and symptoms (Ayus al, Medicine, 1982)

    Fevers and chills

    Flank or Lumbar pain



    Oliguria is RARE

  • Urinary findings:

    Gross hematuria (19%)


    (+) urine culture (70%)

    Proteinuria (81%) (TYPICALLY sub-nephrotic)

2. Imaging:

  • Intravenous Urography (IVP)

    ‘blunt’ tipped calyces = EARLY FEATURE

    Sloughing of papilla may yield the typical ‘mdeullary ring’ sign = LATE FINDING

    Intravenous Urography not used very often anymore

  • Ultrasononography

    May be normal EARLY in the course

  • Contrast Enhanced CT (multidetector)

    Hypoattenuated lesions in papillary regions

    Papillary calcifications may be seen with analgesic abuse

3. Treatment:

  • Treat the associated conditions(s)

Radiation Nephropathy (XRT Nephropathy)
  • The kidneys are very radiosensitive and the dose-limiting organs forradiotherapy during total body irradiation (TBI) for bone marrowtransplantation and treatment of: gastrointestinal cancers, gynecologiccancers, lymphomas and sarcomas

  • Incidence is likely underreported 2nd to long latency period between exposure and progression

  • Radiation was previously used to treat transplant rejection before the advent of better immunosuppression drugs

1. Clinical Presentation:

  • Progressive kidney disease 2nd to reduction of renal mass

  • HTN

    May be malignant

    Rare phenomenon of radiation-induced renal artery stenosis (proximal lesions)

  • Anemia out of proportion to the severity of renal disease

    Normochromic, normocytic with a low reticulocyte count 2nd to damage to Erythropoeitin (EPO) producing cells

  • Proteinuria (mild–nephrotic syndrome)

  • May be either acute or chronic

    If acute, may create picture of thrombotic microangiopathy (TMA) which has been termed Bone Marrow Transplant Nephropathy

    Typically occurs within 3-4 months post irradiation

    May be predicted by ACE gene polymorphisms

  • Chronic radiation nephropathy

    Occurs months-years post irradiation

2. Dose:

  • In Radiation Nephropathy, threshold dose of radiation after single kidney irradiation is ~ 23 Gy and 20 Gy if both kidneys are irradiated

3. Renal Biopsy:

  • Mesangiolysis

  • Radiation induced glomerular changes (within the glomerular capillary) are diffuse and are typically seen before tubular changes

  • Tubulointerstitial scarring and atrophy

    Correlates with the degree of renal dysfunction

  • Arteriolar and arterial thromboses

4. Treatment:

  • Blood pressure control with ACE inhibitors or Angiotensin Receptor Blockers (AT
    1 blockers)

    AT1 blockade may be more effective than ACE inhibition in prevention of XRT Nehropathy

  • Limiting the dose of radiation

  • Dose recommendations are only suggested as few studies exist

    Mean kidney dose in bilateral kidney irradiation should be < 10 Gy during TBI and < 18 Gy in non-TBI

  • Appropriate shielding of kidneys during TBI

  • Kidneys may move inferiorly with respiration (up to 7 cm)

Vesicoureteral Reflux

1. Definition = abnormal, retrograde flow of urine from the urinary bladder into the proximal urinary tract

  • COMBINES BOTH an anatomic abnormality at the ureterovesical junction (incompetent antireflucx mechanism) and generalized dysfunction of the lower urinary tract

  • May be primary (abnormal ureterovesical junction) or secondary (2ndto abnormally high pressure within the bladder due to: neurogenic bladder, posterior urethral valves or occult bladder obstruction)

  • Alternative View = VUR does NOT cause CKD but is a marker of a defect in renal development secondary to abnormal formation of the renal parenchyma (renal hyoplasia ± dysplasia)

2. Clinical Presentation:

  • Present in up to 30-50% of children with UTI

  • Female predominance ~ 4:1

  • Caucasian:African American 10:1

  • Often associated: nocturnal enuresis, GI disturbances and flank pain

  • Physical examination must include:

    Measurement of blood pressure

    Evaluation of flanks and abdomen for tenderness and masses

    Inspection of external genitalia

    Inspection of back for features of spinal dysgraphism (gluteal cleft and cutaneous lesions

  • UTIs

    Typically from intestinal tract flora

    Escherichia coli = most frequent

    80% of cases of VUR are diagnoses after a UTI

    Controversy exists as to whether UTI in children with VUR leads to renal scarring

  • Tubular Dysfunction

    EARLY manifestation

    Defects in urinary concentration

    Severity may correlate with the degree of scarring

  • Renal Failure

    Proposed 2nd to renal scarring and the degree of reflux

    ~ 35% pts have renal failure without preceding infection

    Related to the devlopment of pyelonephritis

    Age at 1st episode of pyelonephritis correlates with development of renal scarring

  • Italkid Project

    Registry of 1,179 pts in Italy

    Primary VUR accounted for 25.4% cases of chronic renal failure

    Estimated risk of developing ESRD by age 20 was 56%

    4 fold increase risk of progression to ESRD if eGFR < 40 ml/min/1.73m2

    Proteinuria was a poor prognostic risk factor and indicative of progressive glomerulosclerosis, especially if (+) HTN

  • HTN

    Incidence is 15-30% children, 30-50% in adults

    2nd to reflux nephropathy

    Highest risk: adolescence and adulthood

    Malignant HTN is unusual but has been reported in younger children

3. Diagnosis and Imaging Studies:

  • International Reflux Grading System

    Depends upon the degree of retrograde filling and dilation of the renal collecting system

    Requires a voiding cystourethrogram (VCUG) (requires urethral catheterization and significant radiation)

    Graded I through V

    Grades I and II often resolve spontaneously within 5 years

  • Radionuclide Cystography (RNC)

    Requires uerthral catheterization but LESS radiation

    May NOT allow for anatomical assessment (bladder and urethral) versus VCUG

    Poor visualization of male urethra

  • Technetium-99m labeled Dimercaptosuccinic Acid Scintigraphy (DMSA)

    Allows for the detection of pyelonephritis and renal scarring

  • Urodynamics

    Up to 76% children with VUR have associated voiding dysfunction

4. American Academy of Pediatrics recommendations:

  • In children between 2 months – 2 years, following the 1st episode of febrile UTI, obtain:

    Renal and bladder ultrasound


    Strength of evidence for obtaining a VCUG in ALL children with a 1st febrile UTI is NOT great

    Risk of parenchymal renal damage and scarring following pyelonephritis is highest in this age group

5. Natural History:

  • Spontaneous resolution of VUR occurs if: unilateral and low grade

  • Persistence is more common if: severe grade, bilateral or renal scarring

  • Females more commonly develop UTIs and were affected by dysfunctional voiding versus males, but NO difference in rates of progression to CKD

6. Familial Association:

  • Found in two-thirds of offspring of a parent with primary VUR

  • 1/3 to 1/2 have an affected sibling

  • Often unilateral and low grade

7. Management:

  • MAIN GOAL: prevention of complications, progressive renal failure leading to HTN and ESRD

  • Treatment is extremely controversial due to lack of long-term data

  • CLINICAL PEARL: bowel and bladder dysfunction must be treated aggressively with bladder training +/- anticholinergic

  • Approach to treatment is based upon:

    Age of presentation

    Likelihood of renal scarring and progression to CKD/ESRD determined by:

    Grade of reflux

    Likelihood of spontaneous resolution

    Presence of voiding dysfunction

    Family and patient preference

  • Medical Management

    Role of prophylactic antibiotics is controversial, based upon the observation that VUR will resolve spontaneously

    International Reflux Study: randomly assigned 306 pts with Stage III-IV VUR to antimicrobial prophylaxis versus ureteral reimplantation

    10 yrs of data for 223 children revealed that renal growth and rate of UTI were similar

    Medically managed pts had MORE febrile infections

    Children with eGFR < 70 ml/min/1.73m2 did well with either medical or surgical management

    Surveillance with aggressive treatment of intercurrent episodes of UTI may be aseffective as medical and surgical intervention with LOW GRADE reflux(Grades I and II)

  • Antibiotic choices

    If < 6 wks of age = Amoxicillin

    If > 6 weeks of age = Trimethoprim-Sulfamethoxazole

    If > 2 months of age = Nitofurantoin

  • Surgical Management

    If anatomic abnormalities, bladder diverticulum or ureterocele, spontaneous resolution will NOT occur

    Surgical ureteral reimplantation:

    Rate of reflux resolution is 95-99%

    There is NO standard algorithm and is often hospital site specific

    Indications may include:

    Grade V reflux with renal scarring

    Anatomic abnormalities

    Febrile UTIs despite prophylactic antibiotics

    Medical non-compliance or inability to tolerate prophylactic antibiotics 2nd to side effects

  • Endoscopic Techniques

    Use of dextranomer-hyaluronic acid (Deflux©) was FDA approved 2001

    Success rates of up to 78.5% in Grades I-II VUR

    Proficiency of the endoscopist is important

    Long term success is not yet proven with ~12% failure at 3 yrs

8. Follow-Up:

  • Close monitoring of height, weight and blood pressure

  • Long term monitoring is suggested by the American Urologic Association (AUA)

  • If urinary symptoms or unexplained fevers, mandatory urinalysis and urine cultures

  • There is LIMITED data to decide when to discontinue prophylactic antibiotics

  • No standard follow-up imaging protocol is recognized

9. AUA Guidelines on the treatment of VUR 2010

  • Based upon systemic reviews of the literature

  • Efficacy of antibiotic prophylaxis could NOT be established with the current data

  • Recommendations for long-term follow-up were included

  • Though the recommendations were evidence based, there was NO grading quality of evidence or strength of recommendation

How to utilize team care?

Specialty Consultations
  • Utilization of specialty consultations is disease specific

  • Often nephrology works side-by-side with urology, especially in obstructive processes: radiation nephritis and papillary necrosis and in the detailed evaluation of patientss with VUR

  • Given the potential for malignancy in patientss with: Sickle Cell Trait (Disease) and Aristolochic Acid Nephropathy/Balkan Endemic Nephropathy, these patients require CLOSE follow-up by urology

Toxicologists and Environmental and Occupational Health Experts
  • Assist in the identification and management of environmental toxins i.e. cadmium and lead

  • Assist in the identification of public health issues related to these substances working closely with government agencies

  • Ensure correct dosing of medications in relationship to eGFR

  • Assist with BOTH pharmacokinetic and pharmacodynamic interactions, especially in relation to HIV and chemotherapeutic medication

Are there clinical practice guidelines to inform decision making?

  • There is limited data regarding Clinical Practice Guidelines to guide management in chronic interstitial nephritis

  • Many studies used in the treatment of CIN are observational

  • There are Clinical Practice Guidelines for the Management of VUR published by the American Urologic Association in 2010

Other considerations

1. DRG:

  • Important to document:

    Underlying systemic process

    Acute or Chronic Process

    Associated conditions: hypertension, fluid overload, mailgnancy

2. Typical Lengths of Stay:

  • Depends upon underlying disease process and associated co-morbidities

What is the evidence?

Sickle Cell Disease

Allon, M. “Renal Abnormalities in sickle cell disease”. Arch Intern Med. vol. 150. 1990. pp. 501-504.

Pham, PT, Pham, PT, Wilkinson, AH, Lew, SQ. “Renal abnormalities in sickle cell disease”. Kidney International. vol. 57. 2000. pp. 1-8.

Scheinman, J. “Sickle cell disease and the kidney”. Nature Clinical Practice Nephrology. vol. 5. 2009. pp. 78-88.


Berliner, AR, Haas, M, Choi, MJ. “Sarcoidosis: the nephrologist's perspective”. AmJ Kidney Dis. vol. 48. 2006. pp. 856-870.

Göbel, U, Kettritz, R, Schneider, W, Luft, FC. “The protean face of renal sarcoidosis”. J Am Soc Nephrol. vol. 12. 2001. pp. 616-623.

Mahévas, M, Lscure, FX, Boffa, J-J, Delatour, V, Belenfant, X, Chapelon, C, Cordonnier, C, Makdassi, R, Piette, J-C, Naccache, J-M, Cadranel, J, Duhaut, P, Choukroun, G, Ducroix, JP, Valeyre, D. “Renal sarcoidosis”. Medicine. vol. 88. 2009. pp. 98-106.

Sjögren's Syndrome

Aasarød, K, Haga, H-J, Berg, KJ, Hammerstrøm, J, Jørstad, S. “Renal involvement in primary Sjögren's syndrome”. Q J Med. vol. 93. 2000. pp. 297-304.

Bossini, N, Savoldi, S, Franceschini, F, Mombelloni, S, Baronio, M, Cavvazzana, I, Viola, BF, Valzorio, B, Mazzucchelli, C, Cattaneo, R, Scolari, F, Maiorca, R. “Clinical and morphological features of kidney involvement in primary Sjögren's syndrome”. Nephrol Dial Transplant. vol. 16. 2001. pp. 2328-2336.

Maripuri, S, Grande, JP, Osborn, TG, Fervenza, FC, Matteson, EL, Donadio, JV, Hogan, MC. “Renal involvement in primary Sjögren's syndrome: A clinicopathologic study”. J Am Soc Nephrol. vol. 4. 2009. pp. 1423-1431.

Analgesic Nephropathy

De Broe, ME, Elseviers, MM. “Analgesic nephropathy”. NEJM. vol. 338. 1998. pp. 446-452.

Gooch, K, Culleton, BF, Manns, BJ, Zhang, J, Alfonso, H, Tonelli, M, Frank, C, Klarenbach, S, Hemmelgarn, BR. “NSAID Use and progression of chronic kidney disease”. Am J Med. vol. 120. 2007. pp. 280.e1-280.e7.

Whelton, A. “Nephrotoxicity of nonsteroidal anti-inflammatory drugs:physiologic foundations and clinical implications”. Am J Med. vol. 106. 1999. pp. 13S-24S.

Lithium Nephrotoxicity

Alexander, MP, Farag, YMK, Rennke, HG, Singh, AK. “Lithium Toxicity: A double-edged sword”. Kidney International. vol. 73. 2008. pp. 233-237.

Grüfeld, J-P, Rossier, BC. “Lithium nephrotoxicity revisited”. Nature Reviews Nephrology. vol. 5. 2009. pp. 270-276.

Presne, C, Fakhouri, F, Noël, L-H, Stengel, B, Even, C, Kreis, H, Mignon, F, Grünfeld, J-P. “Lithium-induced Nephropathy: rate of progression and prognostic factors”. Kidney International. vol. 64. 2003. pp. 585-592.

Phosphate Nephropathy

Gonlusen, G, Akgun, H, Ertan, A, Olivero, J, Truong, LD. “Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing”. Arch Pathol Lab Med. vol. 130. 2006. pp. 101-106.

Heher, EC, Thier, SO, Rennke, H, Humphreys, BD. “Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation”. Clin J Am Soc Nephrol. vol. 3. 2008. pp. 1494-1503.

Markowitz, GS, Stokes, MB, Radhakrishnan, J, D’Agati, VD. “Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure”. J Am Soc Nephrol. vol. 16. 2005. pp. 3389-3396.

Acyclic Nucleoside Phosphonates and Tubular Toxicity

Gupta, SK. “Tenofovir-associated Fanconi syndrome:Review of the FDA Adverse Event Reporting System”.

Herlitz, LC, Mohan, S, Stokes, MB, Radhakrishna, D’Agat, VD, Markowitz, GS. “Tenofovir nephrotoxicty: acute tubular necrosis and distinctive clinical, pathological, and mitochondrial abnormalities”. Kidney International. vol. 78. 2010. pp. 1171-1177. (Nice summary of the clinical and pathologic abnormalities of Tenofovir Nephrotoxicity with characterization of mitochondrial abnormalities on microscopy.)

Izzedine, H, launay-Vacher, V, Deray, G. “Antiviral drug-induced nephrotoxocity”. Am J Kidney Dis. vol. 45. 2005. pp. 804-817.

Mesalamine and Aminosalicylates

Corrigan, G, Stevens, PE. “Review Article: Interstitial nephritisassociated with the use of Mmsalazine in inflammatory bowel disease”. Aliment Pharacol. vol. 14. 2000. pp. 1-6.

Gisbert, JP, González-Lama, Y, Maté, J. “5-Amiosalicylates and renal function In inflammatory bowel disease: a systemic review”. Inflamm Bowel Dis. vol. 13. 2007. pp. 629-638.

Urate Nephropathy

Bellomo, G, Venzanzi, S, Verdura, C, Saronio, P, Esposito, A, Timio, M. “Association of uric acid with changes in kidney function in healthy normotensive individuals”. Am J Kidney Dis. vol. 56. 2010. pp. 264-272.

Johnson, RJ, Kivlighn, SD, Kim, Y-G, Suga, S, Fogo, AB. “Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease and renal disease”. Am J Kidney Dis. vol. 33. 1999. pp. 225-234.

Moe, OW. “Posing the question again: does chronic uric acid nephropathy exist?”. J Am Soc Nephrol. vol. 21. 2010. pp. 395-397.

Obermayr, RP, Temml, C, Gutjahr, G, Knechtelsdorfer, M, Oberbauer, R, Klauser-Braun, R. ” Elevated uric acid increases the risk for kidney disease”. J Am Soc Nephrol. vol. 19. 2008. pp. 2407-2413.

Hypokalemic Nephopathy

Bock, KD, Cremer, W, Werner, U. “Chronic hypokalemic nephropathy”. Klin Wochenschr. vol. 56. 1978. pp. 91-96.

Novello, M, Catena, C, Nadalini, E, Colussi, GL, Baroselli, S, Chiuch, A, Lapenna, R, Bazzocchi, M, Sechi, LA. “Renal cysts and hypokalemia in primary aldosteronism: results of long-term follow-up after treatment”. JHypertens. vol. 25. 2007. pp. 1443-1450.

Immune-related Potassium Losing Interstitial Nephritis (IRPLIN)

Wong, OM, Feest, TG, Maciver, AG. “Immune-related potassium-losing interstitial nephritis: a comparison with distal RTA”. Q J Med. vol. 86. 1993. pp. 513-534.

Idiopathic Hypocomplementemic Immune-Complex-Mediated Tubulointerstitial Nephritis

Kambham, N, Markowitz, GS, Tanji, N, Mansukhami, MM, Orazi, A, D’Agati, VD. “Idiopathic hypocomplementemic interstital nephritis with extensive tubulointerstitial deposits”. Am J Kidney Dis. vol. 37. 2001. pp. 388-399.

Vaseemuddin, M, Schwartz, MM, Dunea, G, Kraus, MA. “Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis”. Nature Clinical Practice Nephrology. vol. 3. 2007. pp. 50-58.

Tubulointerstitial Nephritis with IgG4-related Systemic Disease

Saeki, T, Saito, A, Yamazaki, H, Emura, I, Imai, N, Ueno, M, Nishi, S, Miyamura, S, Gejo, F. “Tubulointerstitial nephritis associated with IgG4-related systemic disease”. Clin Exp Nephrol. vol. 11. 2007. pp. 168-173.

Yoneda, K, Murata, K, Katayama, K, Ishikawa, E, Fuke, H, Yamamoto, N, Ito, K, Shiraki, K, Nomura, S. “Tubulointerstitial nephritis associated with IgG4-related autoimmune disease”. American Journal of Kidney Disease. vol. 50. 2007. pp. 455-462.

Divalent Cation (Heavy Metals) and Nephropathy

Brewster, UC, Perazella, MA. “A review of chronic lead intoxication: An unrecognized cause of chronic kidney disease”. Am J Med Sci. vol. 327. 2004. pp. 341-347.

Ekong, EB, Jaar, BG, Weaver, VM. “Lead-related nephrotoxicity: A review of the epidemiologic evidence”. Kidney International. vol. 70. 2006. pp. 2074-2084.

Evans, M, Elinder, C-G. “Chronic renal failure from lead: myth or evidence-based fact”. Kidney International. vol. 79. 2011. pp. 272-279.

Gonick, HC. “Nephrotoxicity of cadmium and lead”. Indian J Med Res. vol. 128. 2008. pp. 335-352.

Aristolochic Acid Nephropathy (Chinese Herbs) and Balkan Endemic Nephropathy

Debelle, FD, Vanherweghem, J-L, Nortier, JL. “Aristolochic acid nephropathy: a worldwide problem”. Kidney International. vol. 74. 2008. pp. 158-169.

Pitt, JL. “Chinese herb medicines, Aristolochic acid and Balkan endemic nephropathy”. Occup Environ Med. vol. 68. 2011. pp. 237

Schiller, A, Gusbeth-Tatomir, P, Pavlovic, N, Ferluga, D, Spasovski, G, Covic, A. “Balkan endemic nephropathy: a still unsolved puzzle”. J Nephrol. vol. 21. 2008. pp. 673-680.

Stefanovic, V, Polenakovic, M. “Fifty years of research in Balkan endemic nephropathy: Where are we now?”. Nephron Clinical Pract. vol. 112. 2009. pp. c51-56.

Renal Papillary Necrosis

Eknoyan, G, Qunibi, WY, Grissom, RT, Tuma, SN, Ayus, JC. “Renal papillary necrosis: an update”. Medicine. vol. 61. 1982. pp. 55-73.

Jung, DC, Kim, SH, Jung, SI, Hwang, SI, Kim, SH. “Renal papillary necrosis:review and comparison of findings at multi-detector row CT and intravenous urography”. Radiographics. vol. 26. 2006. pp. 1827-1836.

Radiation Nephropathy

Cohen, EP, Robbins, MEC. “Radiation nephropathy”. Sem Nephrol. vol. 23. 2003. pp. 486-499.

Dawson, LA, Kavanagh, BD, Paulino, AC, Das, SD, Miften, M, Li, XA, Pan, C, Ten Haken, RK, Schultheiss, TE. “Radiation-associated kidney injury”. Int J RadiOncol Biol Phys. vol. 76. 2010. pp. S108-115.

Vesicoureteral Reflux

Gargollo, PC, Diamond, DA. “Therapy insight: what nephrologists need to know about primary vesicoureteral reflux”. Nature clinical practice Nephrol. vol. 3. 2007. pp. 551-563.

Peters, GA, Skoog, SJ, Arrant, BS, Copp, HL, Elder, JS, Hudson, RG, Khoury, AE, Lorenzo, AJ, Pohl, HG, Shapiro, E, Snodgrass, WT, Diaz, M. “Summary of the AUA Guidelines in the management of primary VUR in children”. J Urol. vol. 184. 2010. pp. 1134-1144.

Williams, G, Fletcher, JT, Alexander, SI, Craig, JC. “Vesicoureteral reflux”. J Am Soc Nephrol. vol. 19. 2008. pp. 847-862.