Chapter 37. Chronic Tubulointerstitial Nephritis

Chronic interstitial nephritis (CIN) is by definition tubulointerstitial nephritis that has failed to resolve on its own or has been resistant to whatever treatment was rendered after several months or years. However, it can also arise de novo as a consequence of chronic, low-grade, or injurious exposures of the tubulointerstitium to the culprit agent, ie, medication, physical factor, infectious agents, etc. Such exposures may be intermittent or persistent. Histopathologically, it is characterized by the presence of interstitial chronic inflammation, interstitial fibrosis, and tubular atrophy (Figure 37–1).

Depending on the culprit agent, the disease may have a particular predilection for either the proximal tubules, the distal tubules, or both. The functional abnormalities usually depend on the tubular site of involvement, ie, distal tubule dysfunction may be characterized by acidosis and hyperkalemia, as seen in obstructive uropathies, whereas injury involving the renal medulla is characterized by an impaired ability to concentrate urine as seen in sickle cell nephropathy (Table 37–1).

As CIN progresses, there may be concomitant glomerular abnormalities, probably secondary to maladaptive alterations in the glomeruli or a result of the tubulointerstitial processes. At that time, patients may present with nephrotic-range proteinuria, which can cloud the primary underlying disease process.

The various causes of CIN can be classified into several categories (Table 37–2).

Epstein–Barr Virus

The localization of Epstein–Barr virus (EBV) DNA in the proximal tubule cells in patients with CIN of unknown etiology has suggested a causative role for the Epstein–Barr virus. However, further studies need to be done to demonstrate if a true cause and effect of EBV renal scarring actually exists.

BK Virus Nephropathy

In immunosuppressed individuals, such as transplant recipients, BK polyoma virus infection has been shown to cause interstitial nephritis. The virus has been demonstrated in the transitional cells in the urine (so-called ‘decoy cells') via urine microscopy, but correlation with renal allograft function status and histologic evidence of renal involvement is very poor. Accurate diagnosis of BK polyomavirus infection requires a very high index of suspicion. Electron microscopy is very sensitive in depicting the presence of BK virions, but the finding of viral particles is not by itself diagnostic. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.

Clinically, it is difficult to distinguish interstitial nephritis versus acute cellular rejection.

Management of patients with polyoma virus nephropathy is difficult since there is no specific antiviral therapy available at this time. Aside from reducing immunosuppressive therapy, other novel treatments include IVIg and Cidofovir. The latter is also nephrotoxic, and has been described to cause acute interstitial nephritis.

Acute Pyelonephritis

Acute pyelonephritis (discussed in more detail in Chapter 38) is classified under the category of complicated urinary tract infections. Patients clinically present with a combination of symptoms that includes fever and chills, dysuria, urgency, and increased frequency. They commonly complain of flank discomfort with a physical correlate of costovertebral angle tenderness. Urine microscopy usually reveals an active urinary sediment consisting of leukocytes and leukocyte casts, and even red blood cells (RBCs) on occasion.

Histopathologically, there is infiltration of polymorphonuclear cells and lymphocytes and edema grossly distorting the normal tubulointerstitial architecture.

The majority of cases respond to appropriate antibiotic therapy targeting the causative organism, which is most commonly a gram-negative Escherichia coli. In those who do not respond to antimicrobial therapy readily, or who develop recurrent infections, there may be renal scarring and possible progression to chronic pyelonephritis.

Chronic Pyelonephritis

Chronic bacterial infections of the urinary tract are among the most common causes of chronic tubulointerstitial nephritis (CTIN). The majority of these cases are associated with vesicoureteral reflux (VUR), hence the term “reflux nephropathy” (discussed in more detail in Chapter 39). However, for those not associated with VUR, the disease is termed “chronic pyelonephritis.”

Clinically, patients with chronic pyelonephritis present with fever and chills, dysuria, vague flank or back pain, as well as hypertension. Some patients may present with tubular abnormalities such as impaired urinary concentrating ability, hyperkalemia, and salt wasting, all of which reflect distal tubular dysfunction. Chronic or repeated urinary tract infections are predisposing risk factors.

Examination of the urine often reveals an active urinary sediment consisting of leukocytes and leukocyte casts. Grossly, the kidneys appear contracted.

Histopathologically, the findings are similar to other forms of CTIN, with tubular atrophy and interstitial fibrosis. Lymphocytes and mononuclear cells predominate in the chronic inflammatory infiltrative population.

Xanthogranulomatous Pyelonephritis

Persistent chronic pyelonephritis can progress to a localized infection called “xanthogranulomatous pyelonephritis.” Its exact pathogenesis is unknown. Typically, there is an underlying urinary tract obstruction, eg, nephrolithiasis, which is complicated by the infection, leading to ischemia and destruction of renal parenchymal tissue, with granuloma formation subsequent to the accumulation of lipid deposits. These lipid deposits are actually lipid-laden macrophages, called “foam cells.”

The symptoms are similar to those of chronic pyelonephritis, including hypertension. Characteristically, a distinct mass may be palpable over the affected “nonfunctioning” kidney. Urine cultures are usually positive for E coli and other gram-negative bacilli or Staphylococcus aureus.

Computed tomography (CT), the imaging modality of choice, demonstrates that the kidney is significantly enlarged. Other findings include the predisposing renal calculus as well as low-density masses or xanthomatous tissues. Neoplastic renal disease must be excluded among the differentials.

On intravenous pyelography (IVP) the involved kidney may contain a localized “abscess-looking” area that may look like a complex cyst or tumor. This is usually distinguished by either magnetic resonance imaging (MRI) or CT.

Current treatment recommendations consist of appropriate coverage with broad-spectrum intravenous antibiotics combined with total or partial nephrectomy.

Analgesic Abuse Nephropathy

Essentials of Diagnosis

• The most common cause of CIN.
• Long-term ingestion of phenacetin, acetaminophen, aspirin, and caffeine or combinations of such.
• Most common in women in their 60s or 70s with a history of chronic low back pain, chronic or recurrent headaches, and chronic joint pains.
• Hypertension is common.
• Imaging studies: Papillary necrosis on IVP, papillary calcifications and bumpy renal contours on CT scan, and small echogenic appearing kidneys on ultrasonography.

General Considerations

Analgesic abuse nephropathy (AAN) is the most common cause of CTIN. There has been a positive correlation between the incidence of renal disease secondary to analgesic nephropathy and the daily consumption of analgesics, in particular phenacetin and other analgesic mixtures.

In the past, it was believed that only phenacetin-containing analgesics were responsible for the disease, but it has been reported on numerous occasions that all analgesics, including acetaminophen, and aspirin can actually cause the same disease process.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are another common cause of CIN. This is discussed in detail in Chapter 15.

Pathogenesis

The main site of renal injury in analgesic nephropathy is the renal medulla (area of the medullary loops of Henle, the vasa recta, and collecting ducts), primarily because of its inherent low oxygen tension. This is also the region in which toxic metabolites of various analgesic compounds build up as a result of the countercurrent mechanism. As the vasoconstrictive effects on the renal medulla predominate, ischemic injury continues, leading to cortical atrophy and eventual interstitial changes.

Clinical Findings

AAN is most commonly seen in females in their 60s or 70s who have chronic pain syndromes, eg, headaches, joint pains or back pains. Ingestion of 1 g of analgesic preparations daily for more than 2 years is considered the minimum dosage and time required to produce clinical analgesic nephropathy. Peptic ulcer disease and gastrointestinal symptoms are a common occurrence.

Renal dysfunction is manifested by isosthenuria (impaired urinary concentration) as well as impaired sodium conservation that may predispose to intravascular volume depletion. Renal tubular acidification defects are also seen. Urinalysis may show evidence of sterile pyuria, urinary tract infection, microscopic or macroscopic hematuria, and mild proteinuria.

Occasionally, patients can present with flank pain or gross hematuria associated with papillary necrosis. Such papillae can slough off and cause obstructive manifestations. These are usually demonstrated on IVP or ultrasonography. Papillary calcification and characteristic “bumpy” renal contours are usually demonstrated on CT. In some instances, the kidneys can appear bilaterally atrophic or asymmetric in size.

Patients with analgesic nephropathy are also at increased risk for transitional cell carcinoma of the uroepithelium.

The oxidative effects of phenacetin are believed to be responsible for the increased formation of atherogenic low-density lipoprotein (LDL), thereby predisposing patients to an increased risk of premature atherosclerosis with attendant cardiovascular morbidity and mortality.

Treatment

Management is primarily supportive, including discontinuation of the culprit analgesic agent. Even after cessation of the analgesic, close monitoring, especially for the development of new symptoms such as gross hematuria, is recommended due to increased risk of uroepithelial tumors.

Lithium-Induced Renal Disease

Essentials of Diagnosis

• CIN is the most common pathologic finding in those with chronic lithium nephropathy.
• Polydipsia and polyuria are presenting symptoms of nephrogenic diabetes insipidus (NDI).
• Incomplete distal renal tubular acidosis (RTA) in up to 50% of patients.
• Pathology: Cystic dilation of the distal tubules leads to the formation of “microcysts.”
• Increased incidence of uroepithelial tumors.

General Considerations

Lithium has been commonly used in patients treated for bipolar disorders. Chronic lithium ingestion is a known cause of NDI. Lithium enters the collecting tubule cells via the sodium channels; by inhibiting adenylate cyclase and subsequent cyclic AMP (cAMP) production it interferes with the ability of antidiuretic hormone (ADH) to increase water reabsorption. Likewise, it decreases the expression of the water channels (aquaporin 2) in the collecting tubules. A positive correlation has been described between the length of duration of treatment (average 6.5–10 years) with lithium and such impairment of urinary concentrating ability manifested by polyuria (and polydipsia). An incomplete distal (type 1) RTA, secondary to lithium-induced decreased H ATPase pump activity in the distal tubule, has been described.

Lithium has also been associated with hypercalcemia. It has been suggested that it induces morphologic changes in the parathyroid glands, resulting in increased parathyroid volume and parathyroid hormone secretion (hyperparathyroidism), which consequently promote bone resorption and subsequent release of calcium into the bloodstream, leading to hypercalcemia.

Clinical Findings

Pathologically, lithium-induced nephropathy is characterized by the formation of “microcysts” (cortical and medullary tubular cysts) in the distal convoluted tubules and collecting ducts (Figure 37–2). Such distal tubular involvement clinically correlates with NDI, manifested by polyuria and polydipsia.

Typically, renal dysfunction secondary to chronic lithium use is mild to moderate. However, patients with serum creatinine levels greater than 2.5 mg/dL at the time of presentation progress to end-stage renal disease (ESRD) even after cessation of lithium. However, in patients with less severe renal dysfunction, such discontinuation of lithium usually leads to stabilization of kidney function.

Amiloride, a potassium-sparing diuretic, has been shown to reduce polyuria and to block lithium uptake in the sodium channels of the collecting duct. In contrast, although thiazide diuretics can reduce lithium-induced polyuria, they can also cause intravascular volume depletion, which can lead to increased sodium and lithium reabsorption in the proximal tubule, thereby aggravating acute lithium toxicity.

Treatment

For those patients on chronic maintenance therapy with lithium, a regular follow-up of serum creatinine, estimated glomerular filtration rate (GFR), and 24-hour urine volume is recommended. Elevations in creatinine should lead to either appropriate dose reduction or complete withdrawal of the drug.

The average latent period between initiation of lithium therapy and onset of ESRD was 20 years.

Calcineurin Inhibitor Induced

Essentials of Diagnosis

• Commonly seen in recipients of solid organ (kidney, pancreas, heart) transplants, with histopathologic features similar to those seen in chronic rejection.
• Electrolyte abnormalities are common, in particular hyperkalemia and hypomagnesemia.
• Pathology: “Striped” pattern of patchy interstitial fibrosis and tubular atrophy.

General Considerations

Cyclosporine and tacrolimus, which belong to a class of immunosuppressive agents primarily called calcineurin inhibitors, are commonly used in solid organ transplantation. Cyclosporine has also been commonly used in the treatment of various autoimmune diseases. These agents also cause acute and chronic renal failure. The pathogenesis can be attributed to the drugs' predominantly vasoconstrictive effect on the afferent arteriole, thereby causing glomerular ischemia.

Clinical Findings

Pathologically, the tubulointerstitial damage occurs in a band-like pattern, referred to as “striped interstitial fibrosis,” involving the cortex and medulla. Tubular injury secondary to calcineurin inhibitors can lead to hyperkalemia and a non-anion gap metabolic acidosis. Other electrolyte abnormalities include hypomagnesemia, hypophosphatemia, and hyperuricemia.

Treatment

Treatment of renal dysfunction requires a significant reduction in the dose of the offending agent, which often translates to an improvement in GFR. Mycophenolate mofetil and rapamycin are alternative immunosuppressive agents commonly used in transplant recipients.

Interestingly, calcineurin inhibitor-induced nephropathy is rare in bone marrow transplant recipients due to the shorter duration and lower doses of the usual treatment regimens.

Aristolochic Acid Nephropathy or Chinese Herb Nephropathy

Essentials of Diagnosis

• Aristolochic acid nephropathy is commonly seen among users of Chinese herbal medications for weight reduction.
• Nephrotoxicity is usually attributed to “aristolochic acid.”
• Pathology: Hypocellular interstitial fibrosis with marked tubular atrophy.
• Increased incidence of uroepithelial tumors.

General Considerations

Typical changes of CIN have been described in mostly middle-aged women in Belgium who were using Chinese herb pills as part of a weight losing diet regimen in 1992. The culprit active ingredient was discovered to be aristolochic acid, which was not only nephrotoxic, but carcinogenic as well.

Clinical Findings

Interestingly, affected patients have normal blood pressure readings. There is a positive correlation between the total dose of aristolochic acid and the decline in GFR.

Treatment

If untreated, patients usually rapidly progress to ESRD. Histopathologically, a hypocellular interstitial fibrosis with marked tubular atrophy is seen. A short course of oral steroids has been shown to slow progression of renal failure.

Chemotherapy Induced

Changes in CIN have been associated with chemotherapeutic agents, especially those with predominant renal routes of excretion. Cisplatin-induced CIN appears to be mediated by increased production of tumor necrosis factor (TNF)-α. Pentoxyphyllin (a known TNF-α inhibitor) has been shown to prevent such cisplatin-induced injury. Damage to the tubulointerstitial areas leads to salt wasting, which may be complicated by orthostatic hypotension, as well as hypomagnesemia and hypocalcemia. Other CIN lesion-producing chemotherapeutic agents include ifosfamide and carmustine. Findings of interstitial fibrosis and chronic inflammatory changes are quite common.

Treatment entails discontinuing the culprit agent and avoiding coadministration of other agents with potential nephrotoxicities.

Acute Phosphate Nephropathy

Acute phosphate nephropathy is a newly described entity commonly seen in patients after exposure to oral sodium phosphate solutions (OSPS) used as bowel cleansers in preparation for colonoscopy. This is characterized by low-grade proteinuria as well as hyperphosphatemia. Histopathologically, there is evidence of acute and chronic tubular injury with interstitial edema, accompanied by tubular atrophy and interstitial fibrosis. The distinctive feature of this entity is the presence of abundant calcium phosphate deposits in the distal tubules and collecting ducts. The following factors predispose patients to acute renal failure: Volume depletion, advanced age, hypertension, concurrent treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), diuretics and NSAIDs, baseline creatinine elevation, or inappropriate use of OSPS in those with underlying chronic kidney disease (CKD).

Preventive measures include adequate hydration and possibly withholding ACEIs, ARBs, diuretics, and NSAIDs on the day prior to and on the day of colonoscopy. OSPS should be used cautiously in elderly individuals.

Cadmium

Years of prolonged environmental or occupational exposure to cadmium also leads to CIN and eventual progression to renal failure. Proximal tubular dysfunction, presenting as Fanconi syndrome, characterized by glucosuria, aminoaciduria, and tubular proteinuria, is common.

Increased urinary cadmium excretion is characteristic. At present, treatment for cadmium nephrotoxicity is primarily supportive.

Lead

Similar to cadmium, the proximal tubule cells tend to be the site of accumulation for lead, thereby leading to a Fanconi type picture. CIN secondary to lead exposure for several years is characterized histopathologically by progressive tubular atrophy and widespread fibrosis, which clinically translate into a significant decline in GFR. There seems to be an inverse relationship between the serum lead measurement and renal function as estimated by GFR. Hypertension is also quite common.

Lead nephropathy also reduces urinary excretion of uric acid, thereby leading to hyperuricemia and gout. In contrast, acute exposure to high levels of lead is usually characterized by acute onset of abdominal discomfort and encephalopathic manifestations as well as anemia.

The diagnosis of lead nephropathy is established by increased urinary excretion of chelated lead, that is, after administration of ethylenediamine tetraacetic acid (EDTA). Cumulative body stores of lead are estimated by the EDTA mobilization test or by x-ray fluorescence, which determines bone lead content. In the EDTA mobilization test, 2 g of EDTA is administered either by the intravenous or intramuscular route, with subsequent measurement of 24-hour urine lead excretion. Urinary lead >0.6 g/day is considered abnormal. One major limitation of the EDTA mobilization test is that it cannot mobilize lead deposits in bone. Reduced levels of erythrocyte aminolevulinate dehydrase (ALAD) compared to levels of ALAD “restored” by the addition of dithiothreitol may be even more efficient in detecting increased body lead burden in patients with chronic renal failure.

Note that serum levels of lead, although elevated during acute exposure, are not very helpful in the chronically exposed. The explanation for this is that during acute exposure, lead is concentrated in the RBCs, which later die, hence extracting lead into the bones and other tissues. Renal biopsy shows nonspecific findings seen in CIN. The treatment of choice is EDTA chelation therapy or oral succimer, which has been shown to slow the progression of CKD.

Sarcoidosis

Renal involvement in sarcoidosis can occur in a variety of ways. Most commonly, patients have hypercalcemia secondary to increased production of 1,25-dihydroxyvitamin D3 by the activated macrophages in the characteristic granulomatous tissues. Such hypercalcemia can lead to other renal manifestations such as nephrogenic diabetes insipidus, hypercalciuria-related nephrolithiasis, and, in some cases, renal failure.

Sarcoidosis can also present as a form of interstitial nephritis with associated “noncaseating granulomas” (Figure 37–3).

Typical tubular manifestations include mild proteinuria, sterile pyuria, and impaired ability to concentrate urine.

Treatment is with corticosteroids 1 mg/kg/day, which has been reported to lead to improved renal function. More commonly, however, because the renal involvement is long standing, recovery is usually incomplete, even in those treated with steroids.

Sjögren's Syndrome

Sjögren's syndrome-associated CIN characteristically presents as type 1 RTA, with hypokalemia and a normal anion gap metabolic acidosis. Although the mechanism for this is incompletely understood, it is believed to be related to autoantibodies against carbonic anhydrase II. Treatment with high-dose corticosteroids has resulted in a dramatic improvement in renal function.

Tubulointerstitial Nephritis with Uveitis Syndrome

Essentials of Diagnosis

• Presents as acute renal failure.
• Commonly affects young adult females and adolescents.
• Accompanying “uveitis” develops in relation to underlying interstitial nephritis.
• Pathology: Predominance of CD4 and CD8 T lymphocytes in renal biopsy.

General Considerations

Tubulointerstitial nephritis with uveitis (TINU) was first described in 1975. It is usually seen in adolescents and young adults, with a female preponderance and no particular racial predilection.

Pathogenesis

The exact pathogenesis remains unclear, but the predominance of T lymphocytes in the tissues and possible association with Chlamydia and Epstein–Barr virus suggest that delayed type hypersensitivity and suppressed cell-mediated immunity may play major roles.

Clinical Findings

Clinically, patients present with nonspecific signs and symptoms, ie, fever, generalized malaise, anemia, and asthenia. Typically, uveitis of the anterior chamber is seen bilaterally, presenting as redness and pain over the eyes. Occasionally, patients complain of accompanying blurring of vision and photophobia. Uveitis can occur as quickly as 2 months prior to, simultaneously with, or up to 14 months after the onset of interstitial nephritis, presenting as acute renal failure.

Renal manifestations include both proximal and distal tubular dysfunction, ie, tubular proteinuria. Increased urine β2-microglobulin (a marker of tubulointerstitial disease) has been noted. Ultrasonography may reveal enlarged swollen kidneys.

Differential Diagnosis

A definitive diagnosis is established by demonstrating typical findings of interstitial nephritis, ie, tubulointerstitial edema with infiltration of lymphocytes, plasma cells, and histiocytes. A predominance of CD4 and CD8 T lymphocytes, monocytes, and macrophages has been described. Eosinophils and noncaseating granulomas may also be seen.

The above findings combined with the temporal relation to the concomitant uveitis make the diagnosis likely.

Other common causes of tubulointerstitial disease process with uveitis include sarcoidosis and Sjögren's syndrome.

Treatment

Renal disease frequently resolves spontaneously over the course of 12 months without steroid therapy. However, for those with moderately advanced chronic kidney disease, prednisone 1 mg/kg/day (usually 40–60 mg orally daily) can be given for 3–6 months depending on the response, and then tapered subsequently. Note that this steroid regimen is somewhat similar to that given for patients with persistent ATIN, except that the duration of therapy is slightly more prolonged because of more frequent relapses noted with TINU. While the renal manifestations may resolve spontaneously and respond well to a course of systemic steroids, the uveitis often has a chronic or relapsing course that may require more aggressive therapy. For uveitis, topical or systemic corticosteroids have been used.

Prognosis

As in other chronic tubulointerstitial diseases, there is a positive correlation between prognosis and the degree of interstitial fibrosis.

Idiopathic Hypocomplementemic Interstitial Nephritis

This disease is usually seen in older men, and as the name implies, is characterized by decreased levels of C3 and C4 (hypocomplementemia) in the absence of evidence of systemic lupus erythematosus (SLE) or Sjögren's syndrome. Histopathology reveals extensive tubulointerstitial infiltration with lymphocytes as well as Ig and complement deposits; these suggest local immune complex formation as the pathogenetic mechanism. Treatment consists of glucocorticoids and cyclophosphamide.

Hyperoxaluria

Oxalate is normally excreted via renal means. However, when combined with calcium, it becomes highly insoluble. The calcium oxalate product can cause nephrolithiasis and CTIN. The diagnosis is established by demonstrating birefringent positive crystals (using polarized light microscopy) not only in the interstitial spaces but also in the tubular lumens, with surrounding inflammation and interstitial fibrosis.

Commonly seen in those with autosomal recessive, primary hyperoxalurias, affected individuals may present with gross hematuria and renal colic secondary to oxalate stones. The majority of patients progress to ESRD by the second decade of life. The recommended treatment for those with recurrent nephrolithiasis and/or ESRD is combined liver and kidney transplantation.

Ingestion of ethylene glycol (antifreeze) and inhalation of methoxyflurane (an anesthetic agent commonly used in the past) are other sources of oxalate. They both cause severe renal failure and residual tubulointerstitial damage in those who recover.

Interestingly, ingestion of a sour “star fruit,” which is noted for its very high oxalate content, is another cause of acute interstitial oxalate deposition leading to interstitial nephritis and eventual renal failure.

In enteric hyperoxaluria, because of chronic diarrhea, less calcium is available in the intestines to bind oxalate. Because of this, much of the unbound oxalate is reabsorbed and excreted in the urinary tract, thereby increasing urinary oxalate levels. In addition to severe hyperoxaluria, patients may also have secondary hypocalciuria and hypocitraturia. This is commonly seen in those who have undergone extensive small bowel resections or jejunoileal bypass procedures.

Individuals who consume excessive amounts of ascorbic acid can also develop oxalate stones and CIN, as ascorbic acid is metabolized to glyoxylate and oxalate.

Hyperuricemia/Hyperuricosuria

In tumor lysis syndrome (discussed in more detail in Chapter 13) there is massive release of uric acid, thereby accounting for the occurrence of hyperuricemia and hyperuricosuria. Histopathologically, urine uric acid and crystals deposit in the interstitium, leading to tubular atrophy, a predominance of interstitial inflammatory infiltrates, and eventual fibrosis.

Hypercalcemia/Hypercalciuria

Hypercalcemia and hypercalciuria are discussed in more detail in Chapters 6 and 40.

Chronic Hypokalemia

In patients with eating disorders who abuse laxatives and diuretics, chronically low levels of potassium have been described. Chronic hypokalemia has had histopathologic correlates consisting of proximal tubular cell vacuolization, dilated intercellular spaces, and medullary cysts; these clinically correlate with an impaired ability to concentrate urine (nephrogenic diabetes insipidus), conserve salt, and hypertension. It remains unclear, however, how often CIN occurs secondary to chronic hypokalemia.

Endemic (Balkan) Nephropathy

As the name implies, endemic (Balkan) nephropathy (EN) is particularly endemic in the so-called Balkan states, or the former Yugoslavia, Bulgaria, and Romania. No specific etiologic cause has yet been identified, but due to its “specific” geographic distribution, environmental factors have long been suspect. Genetic and immune-related factors have also been identified.

Balkan nephropathy is a slow, yet progressive form of CTIN that eventually leads to ESRD.

Dietary consumption of aristolochic acid (see the discussion above on Chinese Herb Nephropathy) has been linked to this disease and its attendant risk of transitional cell cancer.

Clinically, a characteristic early feature is normochromic normocytic anemia, the degree of which is significantly disproportionate to the stage of CKD. Urinalysis usually shows mild proteinuria (increased urine β2-microglobulin has been noted) with few RBCs and WBCs. Patients tend to be normotensive in the earlier stages of the disease with eventual progression to hypertension in more advanced stages. Grossly, the kidneys may appear symmetrically reduced in size.

An important complication of this disease is the development of uroepithelial carcinoma involving the urinary bladder or one or both ureters and renal pelvis.

Treatment is primarily supportive.

Radiation Nephritis

Radiation nephritis is classified into two categories, based on the onset of symptom presentation: Acute radiation nephritis and chronic radiation nephritis.

Acute radiation nephritis usually presents after 6–12 months of exposure to radiation. Patients usually have edema, hypertension (occasionally accelerated hypertension), as well as marked proteinuria. Normochromic normocytic anemia secondary to intravascular hemolysis (microangiopathic hemolytic anemia) accompanying acute renal failure is common.

Chronic radiation nephritis, however, which usually presents after more than 18 months of radiation exposure, is also characterized by proteinuria, hypertension, and progression of CKD toward ESRD.

Although the exact pathogenesis remains elusive, it is believed that exposure of the kidneys to >1500–2500 rads leads to endothelial cell injury and eventual swelling, which leads to vascular occlusion, congestion, and chronic ischemic injury. Radiation can also cause direct injury to the tubular epithelial cells. Furthermore, patients receiving radiation therapy for some underlying malignancy also receive concomitant chemotherapy. The latter may potentiate the toxic effects of radiation to the kidneys.

Histopathologically, aside from the common findings of tubular atrophy and interstitial fibrosis, there is characteristic thickening of the capillary walls, which may also demonstrate “splitting.” Interposition of deposits between the split layers of the GBM is noticeably similar to that seen in hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), thereby supporting the postulated role of endothelial cell injury, leading to intravascular congestion and chronic ischemic injury, as alluded to earlier.

In bone marrow transplant recipients treated with radiotherapy followed by chemotherapy, ie, cyclosporine, pathologic findings similar to those found in thrombotic microangiopathies are similarly found, as opposed to when only chemotherapy is used.

Prevention is the only way to approach radiation nephritis. Proper shielding of the kidneys, especially in those with underlying CKD should be emphasized. Fractionizing the total irradiation dose into several small doses over several days may also have some merit. Likewise, minimizing the total irradiation dose is also suggested.

For those with radiation nephritis who develop hypertension, an ACE inhibitor is the recommended antihypertensive agent.