Does this patient have chronic interstitial nephritis (CIN)?

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

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

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

Treatment

Conservative
Adequate hydration (usually hypotonic fluids)
Sodium containing fluids may cause sodium retention and edema
Often have a blunted response to loop diuretics

Sarcoidosis

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

Clinical manifestations

Hypercalciuria

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)

Hypercalcemia

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

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

Treatment

-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

Treatment:

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
NSAIDS

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

Imaging

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

Treatment:

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)

Prognosis

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

Treatment:

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

Treatment

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)

Treatment

Adequate hydration
Probenecid (given before and after usage) may limit toxicit
Caution if: eGFR < 60ml/min/1.73m²and 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

Treatment

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/1.73m²versus 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

Lymphopenia

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

Proteinuria

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

Pyelonephritis

E coli = most frequent organism

Urinary Tract Obstruction

Sickle Cell Disease (BOTH trait and disease)

Tuberculosis

Cirrhosis

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

Dysuria

Azotemia

Oliguria is RARE
Urinary findings:

Gross hematuria (19%)

Pyuria

(+) 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
₁blockers)

AT₁blockade 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

VCUG

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/1.73m²did 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

Pharmacists

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.

Sarcoidosis

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.

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Jump to Section

Does this patient have chronic interstitial nephritis (CIN)?

Figure 1.

Chronic interstitial nephritis and systemic disease

Sickle Cell Disease (SCD) (Please see chapter on sickle cell nephropathy)

Sarcoidosis

Figure 2.

Sjögren's Syndrome

Chronic interstitial nephritis and medications

Analgesic Nephropathy

NSAID induced Interstitial Nephritis and Nephropathy

Papillary Necrosis

Lithium (Li3+) and Nephrotoxicity

Phosphate Nephropathy

Acyclic Nucleoside Phosphonates and Tubular Toxicity

Adefovir Dipivoxil

Mesalamine and Aminosalicylate Compounds

Chronic interstitial nephritis and medications

Urate Nephropathy

Chronic Interstitial Nephritis and Immune-Mediated Disease

Chronic interstitial nephritis and immune-mediated disease

Immune-related Potassium-losing Interstitial Nephritis (IRPLIN)

Tubulointerstitial Nephritis with IgG4-related Systemic Disease

Chronic interstitial nephritis and toxins

Divalent Cations (Heavy Metals) and Nephropathy

Balkan Endemic Nephropathy (BEN)

Chronic interstitial nephritis and miscellaneous conditions

Renal Papillary Necrosis (RPN)

Radiation Nephropathy (XRT Nephropathy)

Vesicoureteral Reflux

How to utilize team care?

Specialty Consultations

Toxicologists and Environmental and Occupational Health Experts

Pharmacists

Are there clinical practice guidelines to inform decision making?

Other considerations

What is the evidence?

Sickle Cell Disease

Sarcoidosis

Sjögren's Syndrome

Analgesic Nephropathy

Lithium Nephrotoxicity

Phosphate Nephropathy

Acyclic Nucleoside Phosphonates and Tubular Toxicity

Mesalamine and Aminosalicylates

Urate Nephropathy

Hypokalemic Nephopathy

Immune-related Potassium Losing Interstitial Nephritis (IRPLIN)

Idiopathic Hypocomplementemic Immune-Complex-Mediated Tubulointerstitial Nephritis

Tubulointerstitial Nephritis with IgG4-related Systemic Disease

Divalent Cation (Heavy Metals) and Nephropathy

Aristolochic Acid Nephropathy (Chinese Herbs) and Balkan Endemic Nephropathy

Renal Papillary Necrosis

Radiation Nephropathy

Vesicoureteral Reflux

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