chapter 7: hematologic disorders and kidney disease

Chapter 7: Hematologic Disorders and Kidney Disease

Ala Abudayyeh, MD,* and Kevin Finkel, MD, FACP, FASN, FCCM*†

*Division of General Internal Medicine, Section of Nephrology, University of Texas MD Anderson Cancer Center,Houston, Texas; and †UTHealth Science Center at Houston Medical School, Department of Medicine, Division ofRenal Diseases and Hypertension, Houston, Texas

MULIPLE MYELOMA

PathogenesisMultiple myeloma (MM) is a hematologic malig-nancy involving the pathologic proliferation ofterminally differentiated plasma cells. It is thesecond most common hematologic malignancybehind non-Hodgkin lymphoma, with an annualincidence of 4–7 cases per 100,000 in the UnitedStates. Clinical symptoms are due to osteolysis ofthe bone, suppression of normal hematopoiesis,and the overproduction of monoclonal immuno-globulins that deposit in organ tissues. Clinicalsymptoms include bone pain and fractures, anemia,infections, hypercalcemia, edema, heart failure, andrenal disease.

Kidney involvement and pathologyMore than one-half of patients with MM initiallypresent with varying degrees of AKI. Nearly 20%of patients present with a serum creatinine .2.0mg/dL, and 10% of patients require dialysis onpresentation (1). AKI is associated with highermortality, but this may be reflective of patientswith more advanced disease (2).

The major diseases in the spectrum of myeloma-related kidney disease include cast nephropathy, lightchaindepositiondisease(LCDD),andAL-amyloidosis.Renal biopsy demonstrates the presence of mono-typic light chains on immunofluorescence exam, aswell as characteristic ultrastructural features ofdeposits on electron microscopy. Less commonforms of renal injury include light chain–inducedFanconi syndrome, cryoglobulinemia, prolifera-tive glomerulonephritis, heavy chain depositiondisease, and immunotactoid glomerulonephritis(Table 1) (3).3

Cast nephropathyCast nephropathy has been diagnosed in 41% ofpatients withMMand renal disease (4). Excess light

chains precipitate with Tamm-Horsfall protein(THP) secreted by the thick ascending limb of theloop of Henle and produce casts in the distal tubule.Decreased GFR may increase the concentration oflight chains in the distal tubule and enhance theformation of casts. Therefore, hypercalcemia, vol-ume depletion, diuretics, and nonsteroidal anti-inflammatory drugs can exacerbate renal injury.

In some cases of AKI associated with MM, castformation is rare on renal biopsy. Instead, renalinjury is attributed to the direct toxic effects ofurinary free light chains (FLCs) on proximal tubulecells (5,6). After reabsorption, lysosomal degrada-tion of FLCs can activate the NF-kB pathway lead-ing to oxidative stress with an inflammatoryresponse, apoptosis, and fibrosis. This lesion ischaracterized histologically by loss of brush borderand cell vacuolization and necrosis (7).

The classic presentation is an elderly patient withunexplained renal failure, anemia, and bone painor fractures. Proteinuria, when quantitatively mea-sured with a 24-hour urine collection, is usuallysubnephrotic and primarily composed of mono-clonal light chains (Bence-Jones proteins). Thequalitative measurement of proteinuria using aurine test strip, which mainly detects albumin, isgenerally minimally reactive.

Most patients with myeloma cast nephropathyare diagnosed without kidney biopsy using serumand urine immunofixation and serum FLC analysis(see Chapter 9). When biopsied, casts are eosinpositive, fractured, and waxy in appearance on lightmicroscopy (Figure 1) (8). Multinucleated giantcells may surround casts, and an interstitial

Correspondence: Kevin W. Finkel, MD, FACP, FASN, FCCM,Division of Renal Diseases & Hypertension, UTHealth ScienceCenter at Houston-McGovern Medical School, 6431 Fannin St.,Houston, Texas 77030. Email: [email protected]

Copyright © 2016 by the American Society of Nephrology

American Society of Nephrology Onco-Nephrology Curriculum 1

mailto:[email protected]

inflammatory infiltrate composed of lymphocytes and mono-cytes may also be present. Widespread tubular atrophy andinterstitial fibrosis eventually develops. Immunofluorescencestaining generally demonstrates light chain restriction withinthe casts, although patterns may be mixed or nondiagnostic aswell. Casts have a lattice-like appearance and may containneedle-shaped crystals on electron microscopy. The glomeruliand vessels appear normal, unless LCDD is concurrently pre-sent.

Light chain deposition diseaseLCDD has been diagnosed at autopsy in 19% of patients withMM and renal disease (4). The renal manifestations are mostapparent clinically, whereas light chain deposits within the

heart, liver, spleen, and peripheral nervous systemmay remainasymptomatic. The hallmark of the disease is the developmentof mesangial nodules from mesangial matrix expansionsecondary to the up-regulation of platelet derived growthfactor-b and transforming growth factor-b. The nodules canoccasionally be confused with the Kimmestiel-Wilson lesionof diabetic nephropathy.

Clinically, patients present with proteinuria, renal insuf-ficiency, and a nodular sclerosing glomerulopathy. Severalretrospective reviews have reported on the clinical character-istics of these patients (9,10). The mean age was 58 years withno significant preference with respect to sex. Marked renalinsufficiency was common on presentation, with a medianserum creatinine .4 mg/dL, and renal function rapidly de-clined thereafter. Nephrotic range proteinuria was detectedin 26%–40% of patients and correlated with the degree ofglomerular involvement. Hypertension and microscopic he-maturia were also present in the majority of patients.

Light chain deposition stimulates mesangial and matrixexpansion leading to nodule formation. On light microscopy,mesangial nodules aremore uniform indistribution and size inLCDD compared with diabetic nephropathy (Figure 2) (8).Irregular thickening and double contours of the glomerularbasement membrane may also be present. Eosin-positive de-posits may be seen diffusely throughout the tubular basementmembranes. Immunofluorescence demonstrates a character-istic linear staining of basement membranes with monotypic

Table 1. Kidney manifestations of multiple myeloma

Myeloma cast nephropathyAL amyloidosisLight chain deposition diseaseHeavy chain deposition diseaseImmunotactoid glomerulopathyFibrillary glomerulopathyLight chain Fanconi syndromePlasma cell infiltrationCryoglobulinemiaMembranoproliferative glomerulonephritisMembranous glomerulonephritis

Figure 1. Pathology of myeloma cast nephropathy. (A) Large atypical casts are seen within distal tubular lumina. The casts appearhypereosinophilic with fractured texture and sharp edges. They are associated with giant cell (arrows) and mononuclear cell reaction,acute proximal tubular cell injury, and interstitial inflammation (hematoxylin and eosin, 3,2003). (B) The casts characteristically areperiodic acid–Schiff (PAS) negative (3,2003). (C) Myeloma casts almost always stain for just k or l light chain. This figure shows brightstaining of casts for k (immunofluorescence, 3,4003). The casts were negative for l (data not shown). (D) Occasionally, myeloma castsare composed of small rod- or needle-shaped crystals that fill the distal tubular lumina and, as shown, appear highly electron dense onelectron microscopy (31,8503). Reprinted from reference 8, with permission of the Elsevier Science and Technology Journals.

2 Onco-Nephrology Curriculum American Society of Nephrology

light chains, which are most commonly k restricted. On elec-tron microscopy, granular-powdery deposits are distributedwithin the mesangium and midportion of the glomerular,tubular, and vessel wall basement membranes.

Therapy of LCDD is directed at the underlying myeloma.Cytotoxic chemotherapy followed by hematopoietic stem celltransplantation (HCT) has met with good success (11,12).

AL amyloidosisAL amyloidosis occurs when pathogenic light chains unfoldand deposit as insoluble fibrils extracellularly within tissues. Itis found in up to 15% of patients withMMon autopsy (13,14).In 40% of patients with AL amyloidosis, the bone marrow willhave .10% plasma cells, although only 10% will meet othercriteria for MM (15). Amyloid fibrils may deposit within anyorgan, but most commonly affect the kidneys, heart, liver, andperipheral nervous system.

Patients often presentwith fatigue, weight loss, and nephroticsyndrome. The clinical characteristics of patients with biopsy-proven renal amyloidosisweredescribed ina retrospective reviewof 84 patients at the Mayo Clinic (15). The median age at di-agnosis was 61 years, and 62% were male. The median serumcreatinine on presentation was 1.1 mg/dL. The majority of pa-tients had nephrotic syndrome (86%) with a median 24-hour

protein loss of 7 g/day. RRTwas eventually required in 42% ofpatients, andmedian survival after starting dialysis was less than1 year. In general, cardiac involvement occurs innearly one-thirdof patients and portends a poor prognosis.

AL amyloid presents as an amorphic hyaline substancewithin themesangium, glomerular basementmembranes, andvessel walls. Mesangial involvement may be diffuse or nodular.Amyloid stains positive for Congo red and reveals a charac-teristic apple-green birefringence under polarized light. Im-munofluorescence staining reveals the underlying monotypiclight chain, which has a l: k ratio of 6:1. Electron microscopydemonstrates nonbranching randomly oriented 8- to 10-nmfibrils (Figure 3) (8). Amyloid deposits may appear as sub-epithelial spikes along the basement membrane similar tomembranous nephropathy.

Treatment with high-dose melphalan followed by HCTincreases hematologic response and overall median survival(16). Improvement in renal function highly correlates withincreased survival (17).

Treatment of cast nephropathyGeneral measuresVolume resuscitation to assure optimum hemodynamicsupport and adequate urine output (;3 L/day) are of critical

Figure 2. Pathology of light-chain proximal tubulopathy. (A) Large rod- and rhomboid-shaped hypereosinophilic crystals are seenwithin proximal tubular cells. (hematoxylin and eosin, 3,6003). (B) In this patient with smoldering myeloma who has 20% k-restrictedplasma cells in the bone marrow, the proximal tubular crystals stain strongly for k (as shown) with negative l (not shown) by immu-nofluorescence performed on pronase-digested, paraffin-embedded tissue. The intracellular crystals failed to stain for k or l onstandard immunofluorescence on frozen tissue (not shown; 3,4003). (C) Ultrastructurally, the proximal tubular cells are filled withelectron-dense light-chain crystals with rod, rhomboid, or rectangular shapes. The proximal tubule brush border appears preserved(31,8503). (D) In this case of light-chain proximal tubulopathy, the proximal tubular cells are loaded with large election-densephagolysosomes without crystals (electron microscopy, 32,5003). Reprinted from reference 8, with permission of the Elsevier Scienceand Technology Journals.


importance in the initial management. Based on experimen-tal evidence that furosemide promotes intratubular castformation by increasing sodium delivery to the distal tubule,the use of loop diuretics should be avoided unless there isvolume overload. Hypercalcemia should be aggressivelytreated because it can lead to renal vasoconstriction, volumedepletion, and enhanced cast formation. It has been sugges-ted that urinary alkalinization decreases cast formation byreducing the net positive charge of FLCs and the interactionwith THP (18). However, there is no clinical data supportingthis approach. Given the risk of causing renal calcium pre-cipitation in the setting of hypercalcemia, urinary

alkalinization cannot be recommended. Colchicine wasshown to reduce cast formation through decreasing THPsecretion and binding in rats, but human studies havebeen disappointing (19,20).

Chemotherapy and stem cell transplantationThe key to treating myeloma cast nephropathy is rapidreduction in FLC concentrations. An early decrease in FLClevels is associated with the highest rate of renal recovery. Insevere AKI due to cast nephropathy, a 60% reduction in FLClevels by day 21 after diagnosis is associated with renal recoveryin 80% of cases (21). Previous studies with conventional

Figure 3. Pathology of kidney AL amyloidosis. (A) There is extensive global mesangial and segmental glomerular capillary walldeposition of acellular, PAS-negative amyloid deposits. For comparison, the hyaline casts depicted are PAS positive (3,4003). (B) Bydefinition, amyloid deposits should be Congo red positive (i.e., stain red). The figure shows global glomerular and extensive interstitialCongo red–positive amyloid. (3,2003). (C) Congophilic amyloid deposits characteristically show an apple-green birefringence whenviewed under polarized light (3,2003). (D) On immunofluorescence, amyloid deposits appear smudgy and only stain for one of the lightchains. The figure shows global mesangial and segmental glomerular capillary wall staining for l (3,4003). Staining for k was negative(not shown). (E) A distinctive feature of kidney AL amyloidosis is glomerular amyloid spicules, which result from parallel alignment ofamyloid fibrils in the subepithelial space perpendicular to the glomerular basement membrane (electron microscopy, 320,0003). (F) Onhigh magnification, amyloid fibrils appear haphazardly oriented and measure between 7 and 12 nm in diameter (electron microscopy,326,0003). AL, immunoglobulin light chain; PAS, periodic acid–Schiff. Reprinted from reference 8, with permission of the ElsevierScience and Technology Journals.


chemotherapy protocols demonstrated that high-dose dexa-methasone rapidly reduced FLCs. Newer, novel agents such asthalidomide and the proteasome inhibitor, bortezomib, alsorapidly lower FLC concentrations; this has been referred to as“renoprotective chemotherapy.”

Significant improvement in renal dysfunction has beenreported for MM patients treated with bortezomib-basedregimens (22–24). Reversal of renal dysfunction with borte-zomibmay bemore frequent and rapid thanwith other agents,based on observational analysis. No dose adjustment for renalfunction is necessary for bortezomib.

Thalidomide and lenalidomide are two related chemo-therapeutic agents commonly used in the treatment of MM.Lenalidomide dose must be adjusted for renal dysfunction(25). Thalidomide is not dependent on renal function forclearance and does not require dose adjustment for renalfunction; however, it may predispose to hyperkalemia in thesetting of renal failure (26,27). Regimens with thalidomide orlenalidomide have shown superior effectiveness to traditionaltherapy with alkylating agents in terms of reversing renal dys-function in MM; these agents may be nearly as effective asbortezomib regimens (28). Their effects are likely due to rapidlowering of serum FLC levels.

Hematopoietic stem cell transplantation is an importantand potentially curative therapy in MM; however, patientselection criteria are stringent, and significant renal dysfunc-tion has traditionally excluded patients from transplantation.Recent studies have shown that HCTmay be safe and effectivein highly selected patients with renal failure (29).

Extracorporeal removal of free light chainsLight chains are small-molecular-weight proteins. k lightchains usually circulate as monomers with a molecular weightof 22.5 kDa, whereas l light chains are typically dimeric with amolecular weight of 45 kDa (30). Because of their size, therehas been a keen interest in the use of extracorporeal therapyas a means of FLC removal.

A. Therapeutic plasma exchange (TPE):

Several small trials initially suggested thatTPEwas effective in rapidly

lowering FLC concentrations and improving renal function. How-

ever, these studies were small, single center, and underpowered. The

largest randomized controlled trial of TPE did not demonstrate any

benefit inpatientswithcastnephropathy (31).This studyassessed the

benefit of five to seven TPE sessions in 104 patients (30% were di-

alysis requiring) with presumed cast nephropathy (not all patients

had biopsy confirmation). Therewas nodifference in the two groups

with respect to the composite outcome of death, dialysis, or reduced

renal function at 6months. This lack of benefit may be related to the

volume of distribution of FLCs. Based on their molecular weights,

85% of light chains are confined to the extravascular space (32).

Therefore, a traditional 2-hour TPE session would be ineffective in

removing significant amounts of FLCs because of the excessive re-

bound effect.Most of the previous trials were performed prior to the

availability of bortezomib-containing regimens. In a recent study of

14patientswith presumedmyeloma kidney treatedwith bortezomib

and TPE, 12 had complete or partial renal response by 6 months;

however, there were no control patients (33). Although there is still

interest in TPE as a therapy for cast nephropathy, its routine use

cannot be recommended based on the current evidence.

B. High cutoff hemodialysis (HCO-HD):

More recently interest has developed for another method of ex-

tracorporeal removal of FLCs: HCO-HD. In this technique, a

hemofilter with a large pore size (45 kDa) is used for extended

periods of time to remove FLCs.

In the largest study of dialysis dependent renal failure secondary to

MM, 67 patients were treated with HCO-HD and chemotherapy

(34). Only 57% of patients had a renal biopsy, of which 87% had

cast nephropathy. Most patients (85%) received combination

chemotherapy with dexamethasone and either bortezomib or

thalidomide. The median number of HCO-HD sessions was 11,

and all patients had extended (.4 hour) treatments. Overall, 63%

of the patients became dialysis independent. The factors that

predicted renal recovery were the degree of FLC reduction at days

12 and 21 and the time to initiating HCO-HD. Unfortunately, this

trial did not have a control group to assess the benefit of HCO-HD

compared with renoprotective chemotherapy alone.

It is not known whether HCO-HD offers any additional benefit

over current chemotherapeutic regimens. Randomized controlled

trials proving the benefit of adding HCO-HD to patients with cast

nephropathy treated with current chemotherapy will be necessary

before its routine use can be recommended.

LEUKEMIA AND LYMPHOMA

The development of kidney disease is common in patients withlymphoma and leukemia. As with all hospitalized patients,those with lymphoma and leukemia are at risk for developingAKI from hypotension, sepsis, or administration of radio-contrast, antifungal, and antibacterial agents. With the pres-ence of cancer, renal injury can also result from chemotherapy,immunosuppressive drugs, hematopoietic stem cell trans-plantation, or tumor lysis syndrome. Furthermore, patientsare at risk for renal syndromes specific to the presence oflymphoma or leukemia including various forms of paraneo-plastic glomerulopathies, electrolyte disorders, urinary tractobstruction, lysozymuria, leukostasis, and infiltration of renalparenchyma (Table 2). Several of these manifestations arediscussed elsewhere in the Curriculum.

Lymphomatous infiltrationBackgroundRenal involvement in lymphoma is often clinically silent sopatients can present with slowly progressive CKD attributed toother etiologies. Therefore, a high index of suspicion is neededto make a diagnosis. Patients may present with AKI, but this israre and is most commonly seen in highly malignant and


disseminated disease (35–38). Other presentations includeproteinuria in both the nephrotic and nonnephrotic range,as well as a variety of glomerular lesions including pauci-immune crescentic glomerulonephritis (39). Patients may alsopresent with flank pain and hematuria.

Although a variety of cancers can metastasize to the kidneysand invade the parenchyma, the most commonmalignancies todo so are lymphomas and leukemia. The true incidence of renalinvolvement is unknown because it is usually a silent disease andonly occasionally causes renal impairment. Autopsy studiessuggest renal involvement occurs in 90% of patients withlymphoma,whereas radiographic evidence is significantly lower.

The cause of impaired renal function from lymphomatousinfiltration is poorly understood. Based on biopsy series, pa-tients who present with AKI have predominantly bilateralinterstitial infiltration of the kidneys with lymphoma cells anduniformly have increased renal size on radiographic imaging(40). These findings suggest that increased interstitial pressureresults in reduced intrarenal blood flow with subsequent renaltubular injury. Patients who present with proteinuria, on theother hand, often have intraglomerular infiltration with lym-phoma (40). It is not known how proteinuria develops in thesecases, but the local release of permeability factors and cyto-kines has been suggested (41,42).

DiagnosisThe diagnosis of lymphomatous infiltration is necessarily oneof exclusion because more common explanations are oftenpresent. Renal ultrasonography or computed tomography(CT) scan may reveal diffusely enlarged kidneys sometimeswith multiple focal lesions (Figure 4) (43). However, manytimes, radiology will be unrevealing. In a study of 668 con-secutive patients with lymphoproliferative disease who un-derwent diagnostic imaging with a CT scan, only 3% with

non-Hodgkin lymphoma were found to have kidney abnor-malities (44). Both diffuse enlargement and solitary lesionswere detected. This discrepancybetween radiologic and autopsy/histopathologic results may due to the fact that renal involve-ment is often indolent and only detectable in histopathologicexamination (Figure 5) (43). Due to increasedmetabolic activitywithin lymphomatous deposits, positron emission tomographymay be a more sensitive imaging technique (45). Although de-finitive diagnosis depends on renal biopsy, this procedure oftenis impossible because of contraindications. In such cases, thefollowing criteria support the diagnosis of kidney disease dueto lymphomatous infiltration: 1) renal enlargement without ob-struction; 2) absence of other causes of kidney disease; and 3)rapid improvement of kidney function after radiotherapy orsystemic chemotherapy.

TreatmentThe treatment of lymphomatous involvement of the kidney isdirected at the underlying malignancy. There are numerouscase reports of improvement in renal functionafter initiationofantitumor therapy. In indolentmalignantdisease that isusuallytreated by observation alone, kidney involvement is an in-dication for starting systemic therapy.

Leukemic infiltrationBackgroundLeukemia cells can infiltrate any organ, and the kidneys are themost frequent extramedullary site of infiltration. Autopsystudies reveal that 60%–90% of patients have renal involve-ment (46). On biopsy, cells are usually located in the renalinterstitium, although occasional glomerular lesions are noted(47). Increased interstitial pressure leads to vascular and tu-bular compression and subsequent tubular injury. Occasionalnodular lesions are found, but this is more common withlymphoma.

Table 2. Kidney manifestations of lymphoma and leukemia

Comorbid factorsSepsis and shockHypotensionVolume depletionRadiocontrast administrationChemotherapeutic agentsAnti-infective agentsDrug- induced tubulointerstitial nephritisHematopoietic stem cell transplantationRadiotherapy

Disease-related factorsTumor lysis syndromeThrombotic microangiopathyMalignancy-associated hypercalcemiaParaneoplastic glomerulopathiesUrinary tract obstructionParenchymal infiltrationLysozymuriaLeukostasis

Figure 4. Computed tomography scan of abdomen and pelviswithout radiocontrast showing bilateral kidney enlargement.Reprinted from reference 43, with permission of the ElsevierScience and Technology Journals.


Clinical FeaturesLeukemic infiltration of the kidneys is often an indolent andclinically silent disease. Most often it is incidentally noted afterautopsy or by detection of renal enlargement on ultrasound orCTscan. Although uncommon,many cases of AKI attributableto leukemic infiltration have been described (48–50). Patientsmay also experience hematuria or proteinuria. Occasionallyrenal enlargement is accompanied by flank pain or fullness.There are also reports of patients with chronic lymphocyticleukemia who develop AKI from leukemic infiltration and areinfected with polyomavirus (BK) (51). Urine from patientsdemonstrates viral inclusions in tubular cells (“decoy” cells)and blood is positive for BKviral DNA. Therefore, in leukemiapatients with AKI considered due to leukemic infiltration,evidence for coexisting BK virus infection should be sought.

DiagnosisThe diagnosis of leukemia infiltration as a cause of AKIrequires a high level of vigilance because it is often clinicallysilent, and leukemic patients usually have multiple alternativeexplanations for renal injury. A presumptive diagnosis can bemade if there is no other obvious cause of AKI, bilateral renalenlargement is demonstrated radiographically, and there isprompt improvement in renal function after chemotherapy.Screening for leukemic infiltration with radiographic imagingis not revealing. In a study of 668 consecutive patients withlymphoproliferative disease who underwent diagnostic imag-ing with a CTscan, only 5% with leukemia were found to havekidney abnormalities (45). As with lymphoma, this discrep-ancy between radiologic and autopsy/histopathologic resultsmay be due to the fact that renal involvement is often indolentand only detectable during histopathologic examination.

TreatmentTreatment is directed by the type of leukemia. Although somepatients do not recover, in themajority of cases, renal functiondoes improve as the leukemia responds to systemic treatment.

LysozymuriaLysozyme is a cationic protein produced by macrophages andmonocytes and released in response to bacterial infection. It isfreely filtered by the glomerulus and reabsorbed by theproximal tubule. In certain leukemias, clonal expansion leadsto an excessive production of lysozyme and subsequentproximal tubular injury and AKI (52). Damage to the proxi-mal tubule reduces reabsorption and can result in Fanconisyndrome and nephrotic range proteinuria. The presence oflysozymuria can be confirmed by detection of an increased gglobulin level on serum and urine protein electrophoresis withimmunofixation negative for monoclonal gammopathy (53).Treatment is directed at the underlying malignancy.

LeukostasisPatients with myeloid leukemia and exceedingly high whiteblood cell counts (usually in excess of 100,000 cells/mm3) candevelop organ dysfunction due to intravascular aggregation ofleukemic cells. The pulmonary and cerebral circulations arethe most severely affected, although there are case reports ofpatients developing AKI (54,55). Leukemic cells occlude theperitubular and glomerular capillaries, thereby reducing GFR.Patients may be oliguric, but their renal function often im-proves with therapeutic leukopheresis or chemotherapy.Leukostasis is thought to result from the abnormal morphologyof blast cells and the hyperviscocity of the serum. It has beendescribed in both acute and chronic leukemia. Treatment isdirected at treatment of the malignancy with appropriate che-motherapeutic regimens; in severe cases, therapeutic leuko-pheresis can rapidly lower cell counts.

CONCLUSION

Numerous kidney diseases are associated with hematologicmalignancies unique to this population (Tables 1 and 2). Themost common cause of kidney injury in MM patients is castnephropathy (myeloma kidney). Rapid reduction of

Figure 5. (A) Kidney biopsy stained with hematoxylin and eosin at 6033 magnification. (B) Tissue stained with B cell–specificmarker anti-CD38 at 20033 magnification. Reprinted from reference 43, with permission of the Elsevier Science and TechnologyJournals.


circulating free light chains with newer “renoprotective che-motherapy” can reverse renal failure in the majority of cases.Although infiltration of the kidneys by leukemia or lymphomais almost universal histologically, clinical renal disease is un-common. Given themyriad of potential kidney insults in thesepatients, a high index of suspicion is necessary to diagnoseinfiltration as the cause of renal dysfunction.

TAKE HOME POINTS

c Cast nephropathy is the most common cause of renal failure in patients

with multiple myeloma.

c Rapid lowering of free light chains with “renoprotective” chemotherapy

can reverse renal failure from cast nephropathy in the majority of cases.

c Based on current evidence, extracorporeal removal of free light chains

with either therapeutic plasmapheresis or HCO hemodialysis cannot be

recommended.

c Leukemic and lymphomatous infiltration of the kidneys is common on

autopsy, although it is usually not clinically apparent.

c Enlarged kidneys on imaging and resolution of AKI after therapy with

systemic chemotherapy or radiation support the diagnosis of kidney

infiltration.

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REVIEW QUESTIONS

1. An 80-year-old patient with multiple myeloma presentswith serum uric acid of 12.0 mg/dL, serum calcium of 11.0mg/dL, and a phosphate of 8.1 mg/dL. Serum creatinine is4.0 mg/dL, and free l light chains are 3,700 mg/L. WhichONE of the following therapies is contraindicated in thispatient?

a. Urinary alkalinizationb. Intravenous salinec. Rasburicased. Allopurinol

Answer: a is correct. There is a lack of evidence to supportthe use of urinary alkalinization to decrease cast formation byreducing the net positive charge of FLCs. In addition, there isan increased risk of renal calcium precipitation with the pres-ence of hypercalcemia.

2. A 57-year-old man with no medical history is diagnosedwith chronic lymphocytic leukemia with Richter’s trans-formation and presents to the emergency room with cre-atinine of 3.61mg/dL and white blood cell count of 20,000/mm3. The patient has undergone a renal ultrasound in-dicating slightly enlarged kidneys 13 cm bilaterally. Onexamination he was noted to have hepatosplenomegaly.Urinalysis was negative for proteinuria and hematuria. Heis planned for chemotherapy pending a renal consult forhis rise in creatinine. Which one of the following likelyexplains his renal injury?

a. Urinary obstruction related to retroperitoneal lymph-adenopathy

b. Tumor lysis syndromec. Leukemic infiltration of the kidneyd. Membranoproliferative glomerulonephritis with C3

and monoclonal immunoglobulin deposition

Answer: c is correct. It is likely leukemic infiltration inthe setting of enlarged kidney and hepatosplenomegaly withthe lack of other possible etiologies for the patient’s renaldysfunction.

3. A 74-year-old man with chronic myelomonocytic leuke-mia with a long-standing history of hypertension andhyperlipidemia is seen in the clinic. Peripheral bloodmonocyte count is .1,000/mm3, and splenomegaly isnoted. His creatinine has started to rise in the last 6 monthsto 2.0 mg/dL from a baseline of 1.3 mg/dL. Urinalysis in-dicated 31 protein and 31 glucose. His labs included thefollowing: white blood cells, 50,000/mm3; hemoglobin, 9.0g/dL; platelets, 60,000/mm3; serum potassium, 3.0 mEq/L;calcium, 8.0 mg/dL; phosphorus, 1.8 mg/dL; serum glu-cose, 80 mg/dL. Renal ultrasound showed normal sizekidneys and no hydronephrosis. Which ONE of the fol-lowing is the likely cause of this patient’s renal dysfunction?

a. Infiltrative disease secondary to underlying leukemiab. Membranous glomerulopathy secondary to neoplasmc. Renal vein thrombosisd. Lysozyme-induced kidney injury

Answer: d is correct. Lysozyme-induced kidney injury hasbeen underdiagnosed and underrecognized. Uncontrolledproduction of lysozyme secondary to underlying malignancypredisposes the patient to the damage to the proximal tubulereduces reabsorption of electrolytes and can result in Fanconisyndrome and nephrotic range proteinuria. A clue to Fanconisyndrome is glycosuria with normal serum glucose level.On electron microscopy, the kidney biopsies have shown anincrease in number and size of lysosomes in the proximaltubules.

4. A 56-year-old woman with a history of diabetes and hy-pertension (HTN) presented to the hospital with AKI,calcium of 12.0 mg/dL, hemoglobin of 10.0 g/dL, and se-rum albumin of 3.5 g/dL. Urinalysis revealed a specificgravity 1.015 with trace protein on dipstick examinationand occasional granular cast on microscopic examination.Renal ultrasonography revealed normal-sized kidneyswithout hydronephrosis. Creatinine was noted to be at 5mg/dL, and blood urea nitrogen was 82 mg/dL with anormal baseline 6 months ago. Because there was a highsuspicion for multiple myeloma, the patient had a serumfree light chain (FLC) assay to determine monoclonality,and the free serum l light chains were 1,500 mg/L. Whichof the following treatments is indicated for AKI due to castnephropathy?

a. Chemotherapyb. Hemodialysis using dialyzers that have a high-molecular-

weight cutoffc. Plasma exchange therapyd. All of the above

Answer: a is correct. Based on the current evidence, per-forming plasma exchange and high cutoff hemodialysis totreat cast nephropathy cannot be recommended. Significantand rapid reductions in FLC concentrations using “reno-protective chemotherapy” have been shown of benefit in pre-serving renal function.

5. A 63-year-old man with a medical history of well-controlleddiabetes and hypertension presents with a creatinine of 2.0mg/dL, weight loss, fatigue, edema, and worsening periph-eral neuropathy. He was noted to have a serum albumin levelof 3.0 g/dL, and spot urine protein to creatinine ratio of 2 g,with no red blood cells in the urinalysis. Liver functionstudies were normal. He had a negative skeletal survey, and abone marrow biopsy showed normal cellularity with 1%plasma cells. Serum protein electrophoresis indicated IgA lM-protein. Due to the possibility of amyloidosis, the patientunderwent a kidney biopsy which showed a mesangial areaexpanded by amyloid fibrils. If the patient had AL-type


amyloidosis, what is the most appropriate intervention(s)that would improve overall survival?

a. Chemotherapy to reduce monoclonal protein over-production

b. Plasma exchange to reduce circulating FLC levelsc. High-dose melphalan followed by autologous hema-

topoietic stem cell transplantd. Hemodialysis using dialyzers with high-molecular-

weight cutoff

e. Chemotherapy plus extracorporeal removal of the IgFLC

Answer: c is correct. Based on retrospective studies, pa-tients with AL amyloidosis whom underwent stem cell trans-plant have been shown to have improved overall survival andimproved quality of life compared with those undergoingchemotherapy alone. There is no role for plasma exchangeor hemodialysis with a high cutoff filter in the treatment ofamyloidosis.


chapter 7: hematologic disorders and kidney disease

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