ASN Clinicopathologic ConferenceAjay K. Singh* and Lorraine C. Racusen†

Clin J Am Soc Nephrol 6: 2722–2728, 2011. doi: 10.2215/CJN.05300611

IntroductionA 39-year-old African-American man presents withan upper respiratory infection, and urinalysis reveals4� proteinuria, trace blood. Serum creatinine is 1.7mg/dl. He is referred for nephrology consultation.The past medical history is notable only for a chronicskin infection that is being treated with tetracycline.There is no known history of diabetes, sickle celldisease, or hypertension. He has no known drug al-lergies. The social history is remarkable for the patient’soccupation in battery recycling. He is single and in amonogamous sexual relationship. He denies use of in-travenous drugs, cocaine, alcohol, and tobacco. The fam-ily history is negative for kidney disease. His mother hashypertension. On detailed review of systems, the patienthas no physical complaints and specifically denies legswelling, joint pain, skin rashes, dysuria, hematuria,difficulty passing urine, passage of stones, pain, fever,and night sweats.

On physical examination, he appears well. His vitalsigns include a temperature of 35.7°C, BP of 140/80mmHg, and a heart rate of 82 beats per minute. Hisneck is supple, and there is no lymphadenopathy. Hiscardiac and pulmonary examinations are normal.There is no hepatosplenomegaly. He has no signs ofedema, arthritis, or rash. The laboratory data are sum-marized in Table 1.

Dr. Ajay K Singh. To summarize, this is a 39-year-old African-American battery recycler with kidneydisease that was detected during routine evaluationof an acute respiratory infection. The renal dysfunc-tion and the proteinuria could be compatible witheither a tubulointerstitial or a glomerular etiology.Glomerular range proteinuria is usually �3 g/24 h,whereas “tubular” range is in the 1 to 2 g/24-h range.Since our patient has a urinary protein excretion of2 g/24 h, I favor either a tubulointerstitial processor, at most, a mild glomerular disease. The absenceof any prior measures of renal function makes itdifficult to assess acuity. I favor a more acute orsubacute process because of the absence of broadurinary casts and lack of metabolic and hematologicderangements common in a more chronic process(hypobicarbonatemia, low normal calcium and ele-vated phosphorus, and anemia). Compatible withacute etiology, the renal ultrasound shows rela-tively intact kidney size (Table 1).

My differential diagnosis is listed in Table 2. Thehistory of a chronic skin infection raises the possi-

bility of reactive amyloidosis. The occupational his-tory of recycling batteries suggests possible expo-sure to heavy metals such as lead or cadmium.Common things being common, focal segmentalglomerulosclerosis and membranous nephropathyneed to be considered. Review of the laboratorydata reveals a low anion gap and abnormalitiesconsistent with incomplete Fanconi syndrome, rais-ing the possibility of exposure to outdated tetracy-cline or a proximal tubulopathy from a paraprotein.

High rates of type AA amyloidosis have been re-ported in patients with chronic suppurative skin in-fections. Menchel and co-workers (1), in a prospectivesurvey of 150 addicts examined at autopsy, reportedseven cases of renal amyloidosis. In all cases, theamyloid was AA-protein-related. These authors sug-gest that 26% of addicts with chronic suppurative skininfections have renal amyloidosis. However, AA am-yloidosis secondary to chronic inflammatory derma-toses, in the absence of drug-associated “popping,” israre (2,3). We are only provided limited informationabout whether the skin infection is of a suppurativenature in this case. As well, the patient denies intra-venous drug addiction and has no physical evidenceof skin “popping.” Consequently, I believe AA amy-loidosis is an unlikely explanation for the patient’spresentation.

This patient has laboratory features consistent withincomplete Fanconi syndrome, reflecting dysfunctionof the proximal tubule. There are many causes forFanconi syndrome (Table 3). It has been known since1960 that breakdown products of tetracyclines usedafter their shelf life are toxic and cause Fanconi syn-drome (4). In 1963, Gross (5) and Frimpter et al. (6)identified the major degradation products present inthe outdated tetracycline capsules. Subsequent ani-mal studies by Benitz and Diermeier (7) evaluated thetoxicity of three separate tetracycline degradationproducts, demonstrating that epianhydrotetracyclinewas the most toxic. In reported cases glucosuria, ami-noaciduria, phosphaturia, and proteinuria occurredin most, if not all, of the patients. Acidosis was com-mon, and azotemia and hypokalemia were some-times observed. Some of these clinical features arepresent in our patient. However, these derivativesof tetracycline develop only in hot, moist, acid con-ditions. Because citric acid is no longer used in theproduction of tetracycline, tetracycline-associatedFanconi syndrome is now rare. I would be very

*Renal Division,Brigham and Women’sHospital and HarvardMedical School,Boston, Massachusetts;and †Department ofPathology, The JohnsHopkins UniversitySchool of Medicine,Baltimore, Maryland

Correspondence: Dr.Ajay K. Singh, RenalDivision, Brigham andWomen’s Hospital,Medicine / BuildingMRB Room 404B, 75Francis St, Boston, MA02115. Phone: 617-732-5951; Fax-617-732-6392; E-mail:asingh@partners.org

2722 Copyright © 2011 by the American Society of Nephrology www.cjasn.org Vol 6 November, 2011

Special Feature

surprised if this was the explanation for our patient’spresentation.

The occupational history of battery recycling raises thespecter of heavy-metal poisoning from lead or cadmium asa possible cause of his renal disease. Gonick provides anexcellent review of this topic (8). We are not told about thetype of batteries being recycled, or the duration of expo-sure. Nor, for that matter, do we know whether the patientworked in an open smelter, where he could have beenexposed to one or more heavy metals, or in a modernfactory. Since almost 90% of lead acid batteries are recy-cled, there is a possibility of lead exposure in this patientbecause of his occupation.

Lancereaux was the first to report lead nephrotoxicity ina paper published in 1863 (9). He noted substantial atrophyof the renal cortex and tubular fibrosis in the kidney in anartist who habitually held paintbrushes in his mouth. Inthe late 1920s, an epidemic of chronic nephritis due tochildhood lead poisoning brought to light the full spec-trum of lead-induced nephropathy (10). Subsequently, re-ports of lead nephropathy have appeared among distillersof illegal corn whiskey in the United States (11,12) andamong industrial lead workers (13). Nowadays, lead ne-phropathy from the western hemisphere is largely histor-ical since industrial hygiene has markedly improved. In

our patient, lead nephropathy is implausible because of theabsence of certain clinical features that are sine qua non forthe diagnosis, including hypertension, gout, slowly pro-gressive decline in kidney function with minimal protein-uria, an elevated uric acid level, and contracted kidneys onultrasound. Renal dysfunction, in our case, appears sub-acute or acute in tempo, hypertension and gout are absent,proteinuria is significant, uric acid level is on the lowerside, and kidney size is normal. All of these make leadnephropathy an unlikely diagnosis.

Again, because of his occupation, I also considered thepossibility of cadmium nephrotoxicity, which can causerenal dysfunction and Fanconi syndrome (8,14,15). Acuteexposure to cadmium fumes may result in flu-like symp-toms, including chills, fever, and muscle aches, sometimes

Table 1. Laboratory data

Urinalysis: 2 � �protein, occasional RBC, 3–5 WBC, 0 casts, glucose 2�, ketones negativeSodium 137 mEq/L, potassium 4.3 mEq/L, chloride 101 mEq/L, bicarbonate 29 mEq/L. Serum creatinine 1.7 mg/

dl, blood urea nitrogen 15 mg/dl, creatinine clearance 52 cc/min. Glucose 90 mg/dlTotal bilirubin 0.8, calcium 9.8, phosphorus 3.4, cholesterol 245, uric acid 3.2. AST 29, ALT 39, alkaline

phosphotase 84, triglycerides 150Hemoglobin 13.9 g/dl, hematocrit 45%, white blood count 3.1 K, platelets 283,000RPR nonreactive. PSA 0.7.ANA 1:80 speckled nucleolar pattern, anti-DNA negative. Hepatitis B surface Ag and Ab negative, hepatitis C Ab

negative, HIV negative, RPR negative. ESR 13.C3 132, C4 60.24-h urine volume 800 cc, creatinine 1.4 g, protein 2 g/day.SPEP–TP 7.8, albumin 3, alpha-1 globulin 0.2, alpha-2 globulin 0.7, beta-globulin 1.3, gamma-globulin 1.0.Imaging: chest x-ray normal; sonogram without hydronephrosis, kidneys 12.8 and 11.7 cm. A renal biopsy is

performed.

AST - aspartate aminotransferase; ALT - alanine aminotransferase; RPR - Rapid plasma reagin test; PSA - Prostate-specific antigen.

Table 2. Differential diagnosis

Amyloidosis AA secondary to suppurative skininfection

Heavy-metal-associated renal diseaselead or cadmium

FSGSProteinuric glomerular diseaseOutdated tetracyclineAmyloid AA, amyloid AL, monoclonal

immunoglobulin deposition diseaseKappa light chain tubulopathy with incomplete

Fanconi syndrome and possibly light chaindeposition disease glomerular disease

FSGS, focal segmental glomerulosclerosis.

Table 3. Classification of Fanconi syndrome

Inheritedinborn errors of metabolismhereditary fructose intolerancegalactosemiaWilson’s diseasecystinosis

AcquiredDrugs

outdated tetracyclineaminoglycosidescisplatinifosfamide6-mercaptopurinvalproic acidtenofovir

Toxinsmercuryleadcadmiumuranium

Tubular toxicitymultiple myelomaamyloidosislight chain nephropathybenign monoclonal gammopathy

Clin J Am Soc Nephrol 6: 2722–2728, November, 2011 CPC, Singh and Racusen 2723

referred to as “the cadmium blues” (14). More chroniccadmium exposure causes chronic respiratory problemssuch as emphysema, rhinitis, and anosmia. In this case,there is no history of acute occupational exposure and ourpatient did not present with a chronic respiratory ailment.Furthermore, patients with cadmium toxicity frequentlyhave evidence of osteomalacia. The best example of cad-mium intoxication of a large population is itai-itai-byo, or“ouch-ouch” disease, so named because of the cripplingand painful osteomalacia (8,16), endemic to the Jinzu Riverbasin in Japan. The typical patient was a middle-agedpostmenopausal, multiparous woman who had lumbarpains, leg myalgia, a duck-like gait, and typical findings ofosteomalacia. I very much doubt that cadmium is the causeof this man’s presentation, because modern industrialpractices have minimized occupational exposure to cad-mium, and this patient does not have prominent chronicrespiratory or bone-related symptoms.

Rather than a tubulointerstitial etiology, one could arguethis patient has an early glomerular lesion. The presence ofproteinuria would be consistent, but the 2 g per day ofproteinuria would not be typical, unless one invoked thepossibility of secondary focal segmental glomerulosclero-sis (FSGS) or mild idiopathic membranous nephropathy.The history does not support secondary FSGS or membra-nous nephropathy as etiologies; both are unlikely in ourpatient.

The laboratory workup provides us with two relativelysubtle laboratory abnormalities that cannot be ignored andare key to my diagnosis. First, the low anion gap, andsecond, the glucosuria and the lowish phosphorus and uricacid levels suggesting incomplete Fanconi syndrome. Alow-serum anion gap is an uncommon finding. Data fromtwo large clinical laboratories suggest that the prevalenceof a low anion gap is between 0.8% and 3% (17,18). Thecauses of a low-serum anion gap are discussed in detailelsewhere (19). The most common reason for a low aniongap is laboratory error (20). Other causes include an in-crease in unmeasured cations or a decrease in unmeasuredanions. An IgG or IgA paraproteinemia will cause devia-tions in the serum anion gap. IgA tends to be anionic andincreases the anion gap. In general, IgG tends to be cat-ionic, and there is a strong inverse correlation between thelevel of the serum anion gap and the concentration and netpositive charge of IgG paraproteins. The glucosuria in theabsence of hyperglycemia, and the lowish serum phospho-rus level and the low uric acid level, are compatible withFanconi syndrome, likely of the incomplete type, becausenot all of the features of the Fanconi syndrome are evidentin our patient.

In 1954, Sirota and Hamerman were the first to publish areport of an adult with Fanconi syndrome and multiplemyeloma (21). Many reports and series characterizingadult Fanconi syndrome in patients with a paraproteine-mia have since been published. A common finding is thedeposition of crystalline material in lysosomes in proximaltubular epithelial cells and a clinical presentation of Fan-coni syndrome. In rare cases, there is deposition into his-tiocytes and the condition is termed crystal-storing histio-cytosis, with a clinical picture dominated by acute kidneyinjury, rather than Fanconi syndrome. Occasionally, there

is even more widespread renal involvement with crystaldeposition in renal tubular epithelial, visceral epithelialcells, parietal epithelial cells, and, even more rarely, in-volvement of mesangial cells and glomerular endothelialcells.

Maldonado et al. (22) published the first substantive se-ries of proximal tubulopathy with kappa-associated crys-talline deposition. Bence Jones protein of the kappa typewas a constant finding. However, just like the current case,there were no serum protein monoclonal abnormalitiesdetected. In half of the patients, crystalline cytoplasmicinclusion bodies were present in lymphoplasmacytic bonemarrow elements and renal tubular cells. More recently,Messiaen and co-workers (23) reported a series with het-erogeneity in the clinical features. The majority of patients(seven of the 11) had Fanconi syndrome and low-massmyeloma or monoclonal gammopathy of undeterminedsignificance (MGUS). However, three patients who pre-sented with full-blown Fanconi syndrome had myelomakidney; one patient of this group also had numerous crys-tals in proximal tubule cells. One of the 12 patients withFanconi syndrome had no evidence of crystals in proximaltubule cells, even after electron microscopy. Contrastingwith the clinicopathologic heterogeneity, all of the patientshad a paraprotein of the kappa type, and eight of ninebelonged to the V kappa I variability subgroup, whichindicates that Fanconi syndrome light chains are related bythe sequence of their variable regions.

The largest reported series of patient’s with Fanconisyndrome originates from the Mayo Clinic. Ma et al. (24)presented the clinical features and outcomes in 32 patientsdiagnosed with Fanconi syndrome. In their series, 31% hadmultiple myeloma, 6% had Waldenstrom macroglobuline-mia, 19% had smoldering multiple myeloma, and 44% hadMGUS. A monoclonal light chain was detected in the urineof all patients at diagnosis; 91% had kappa light chains,and the other 9% had lambda light chain Bence Jonesproteinuria. Notably, and very much like our patient, atthe time of diagnosis, a serum monoclonal protein wasfound in only 69% of patients and a positive SPEP is notalways seen. Ma et al. (24) also reported that incompleteFanconi syndrome was the rule rather than the exception.While glucosuria was a constant finding, hypokalemia(44%), hypophosphatemia (50%), and hypouricemia (66%)were observed in only a fraction of patients. Of the 32patients, 17 had a renal biopsy performed, and eight hadcharacteristic crystal structures in the cytoplasm of theepithelial cells of the proximal renal tubules. Taken collec-tively, then, the presence of an IgG kappa paraproteinemiaprovides a parsimonious explanation for most, if not all, ofthe clinical findings.

The pattern of the renal disease in dysproteinemic dis-orders depends on where the paraprotein deposits in thekidney (Table 4). This, in turn, determines the clinicalpresentation. Heher et al. and Markowitz et al. provideexcellent reviews on this topic (25–27). A kappa light chainnephropathy results from deposition in the glomerularbasement membrane and presents with proteinuria or thenephrotic syndrome. Rarely, a proliferative glomerulone-phritis has also been reported. A kappa tubulopathy pre-senting with Fanconi syndrome may occur when the prox-

2724 Clinical Journal of the American Society of Nephrology

imal tubular cells reabsorb the kappa light chain, which,because of unique properties, is toxic to the lysosome. Incontrast, light chain in the tubular lumen, with binding toTamm-Horsfall protein, causes obstructive acute kidneyinjury, clinically recognized as myeloma kidney. The spe-cific type of paraprotein influences the distinctive patternsof deposition. In a now-classic paper, injection of humanBence Jones proteins into mice reproduced the specificpatterns of cast formation, basement membrane deposi-tion, or fibril formation seen clinically (28). Amyloid depo-sition most commonly results from lambda paraproteine-mia. The isoelectric point (pI) of the light chain appears tobe important. Paraproteins with a relatively high pI (�5.8to 6) in an acidic urine pH in the distal nephron have anincreased tendency to bind with anionic Tamm-Horsfallmucoprotein forming obstructing casts. The molecular fea-tures of the paraprotein correlate with the patterns ofdeposition. Kappa light chain nephropathy usually reflectsstructural determinants coded by V�1 or V�4. Fanconi’ssyndrome is almost always from a V�1, with specificamino acid substitution causing incomplete catabolism(protease resistance) (29,30).

What are the potential pitfalls with my line of reasoning?The normal serum protein electrophoresis (SPEP) may behard to square with my assertion that the low anion gap isdue to IgG paraproteinemia. However, SPEP is insensitivefor the detection of low concentrations of paraprotein com-pared with either immunofixation electrophoresis or mea-surement of serum-free light chains (31). In a paper byKeren et al., monoclonal gammopathy was correctly de-tected by SPEP only 88% of the time (32). My explanationfor the “negative” SPEP is that the paraprotein has a veryhigh affinity for the kidney, a feature that has been re-ported previously. I am postulating that the low levels inthe plasma could have resulted from the kidney absorbingall of the circulating, highly reactive, and nephrotoxic para-protein. A very small amount of very cationic paraproteincould have caused the low anion gap. On a separate butrelated note, it is also possible that a low albumin (thealbumin was 3 on the SPEP) could have accounted forsome lowering in the anion gap (for every 1-g/dl decre-ment in serum albumin concentration, the serum anion gapis reduced by 2.3 mEq/L). The SPEP result in our patientspoints to a lower-than-normal serum albumin concentra-tion.

In summary, my diagnosis in this patient is an incom-plete Fanconi syndrome from a kappa proteinemia, andmy hope is that Dr. Racusen will show us a kappa chainproximal crystalline tubulopathy on renal biopsy.

Dr. Lorraine Racusen. I have been asked to provide “TheAnswers,” the traditional role for the pathologist in theCPC (clinicopathologic correlation) exercise. The clinicalhistory available for this patient was succinct, as the pa-tient was quickly referred for renal biopsy. However, Dr.Singh has done a superb job of analyzing the available dataand arriving at a diagnosis.

The renal biopsy on this patient was received as twotissue cores, with cortex containing numerous glomeruliand blood vessels. By light microscopy, glomeruli werenormocellular, with delicate mesangium and capillarywalls, which stained with silver and PAS (Periodic AcidSchiff) stains in a normal pattern, without evidence ofabnormal deposits. Interstitial areas contained no inflam-mation or fibrosis. No pathologic changes were seen inarteries or arterioles.

The most striking feature in the biopsy was accumula-tion of eosinophilic crystalline material in tubular epithe-lial cells (see Figure 1). Crystals were silver- and PAS-negative but stained orange on Masson trichrome stain(see Figure 1B). Crystals were largely in proximal tubuleepithelial cells and were associated with cell swelling andfocal cell necrosis. Congo Red stain for amyloid was neg-ative.

Immunofluorescence staining was performed on frozentissue containing seven glomeruli. Protein in tubular epi-thelial cells stained for IgG (1�) and kappa (1�) lightchain, with some albumin as well (2�). Arterioles stainedfor C3 (1�), and some interstitial fibrinogen was detected.Stains for lambda light chain, IgA, IgM, and C1q werenegative. Immunoperoxidase stain for kappa light chainwas positive (see Figure 2), and lambda light chain wasnegative.

Electron microscopy revealed numerous needle-likecrystals and crystalline arrays within proximal tubular ep-ithelial cells (see Figure 3), with rare crystals in mesangialcell cytoplasm. Glomerular epithelial cells were remark-able for focal effacement of foot processes, with somecytoplasmic vacuolization and microvillous change. Nodense, granular, or fibrillary deposits were detected. Im-munoelectron microscopy was performed with gold-la-beled antibody for kappa and lambda light chains. Crystalsstained strongly for kappa light chain, (see Figure 4) withstaining for lambda light chain negative and staining ofnormal control tissue negative.

Since SPEP is not as sensitive as immunofixation (IFE) orassay for free light chains (31,32), and as a follow-up to theelevated �-globulin with asymmetric appearance on SPEP,IFE of the serum was performed and revealed a faint bandin the kappa region. Urine protein electropheresis revealeda spike in the gamma region, with a monoclonal kappalight chain on IFE of the urine. A bone marrow biopsyrevealed greater than 50% plasma cells, kappa light chainpositive. Bone marrow aspirate revealed immature plasmacells with crystalline intracellular granules, apparently im-munglobulin. Congo Red stain for amyloid was negative.

Injury to renal tubular epithelium is a common lesion in

Table 4. Renal disease in patients with a paraproteinemia

Isolated light chain deposition in glomerularbasement membranes

Kappa light chain nephropathyAmyloid nephropathyProliferative GN with monoclonal IgG deposits

Light chain accumulation in proximal tubularepithelial cells

Fanconi syndromeChronic interstitial nephritis

Light chain deposition occluding tubular lumensMyeloma cast nephropathy

Whole immunoglobulin deposition in glomeruliCryoglobulinemiaImmunotactoid glomerulopathy

Clin J Am Soc Nephrol 6: 2722–2728, November, 2011 CPC, Singh and Racusen 2725

light chain-induced renal disease. A common manifesta-tion is failure of reabsorption of small molecules by theproximal tubules, which may result in Fanconi syndrome,but patients may present with acute kidney injury as well.

Free light chains are freely filtered by the glomerulus andavidly absorbed by proximal tubular epithelial cells. Theybind to the megalin-cubulin tandem scavenger receptorsystem (33) and are endocytosed via the clathrin-depen-dent endosomal/lysosomal pathway (34). Intracellularlight chains in turn inhibit Na-K-ATPase in proximal tu-bular cells (35) and lead to a range of cytotoxic effects(36,37).

Nephrotoxic potential is widely variable among lightchains, with kappa light chain more commonly associatedwith tubular injury. Most cases of crystal-associated tubu-lopathy have been associated with kappa light chains,especially the Vh1 subgroup (38), as noted. A transgenic

Figure 1. | (A) Eosinophilic crystalline material in proximal tubularcells (arrows) (H&E staining). (B) Crystals stain orange on trichromestain (arrows) (Masson trichrome).

Figure 2. | Immunoperoxidase stain for kappa light chain revealingpositive staining of intracellular crystals.

Figure 3. | Electron micrograph revealing intracellular spiculatedcrystals in tubular epithelial cells.

Figure 4. | Electron micrograph with immunogold labeling forkappa light chain. Particles are deposited on the intracellular crys-tals.

2726 Clinical Journal of the American Society of Nephrology

animal model created using a V kappa J kappa rearrangedgene from a patient with myeloma-associated Fanconi’ssyndrome demonstrated proximal tubule crystalopathy;crystals diminished on conditional deletion of the humanV kappa (39). Mutations in the CDR L1 loop may conferprotease resistance, with the light chain serving as a nidusfor crystal formation. In other cases, lattice-like arrays orlarge proteinaceous aggregates in lysosomes have beenreported in proximal tubular cells (e.g., Kapur et al. [40]). Insome cases, a pattern of acute tubular injury with promi-nence of lysosomes and atypical lysosomes without crys-tals or inclusions is seen (41). Immunostaining, includingultrastructural immunolabeling, may be critical in makingan accurate diagnosis (42), and the pathologist should bealert to the range of patterns of injury. Crystals in proximaltubular cells are often associated with crystals in bonemarrow cells, as in this case.

Most patients with light chain–associated proximal tu-bulopathy do well in the absence of overt malignancy. Inthe current case, however, multiple myeloma was diag-nosed, with a large number of malignant plasma cells inthe bone marrow. A skeletal survey at the time of diagnosiswas negative for lytic lesions. The patient was started on acourse of chemotherapy, with no malignant cells in a fol-low-up bone marrow biopsy. Creatinine was stable at 1.5,SUN 10. However, at 15 months after diagnosis, the patienthad a bone marrow biopsy with atypical �-positive plasmacells. Approximately 2 years after initial diagnosis, he un-derwent an autologous bone marrow transplant followingcytoreduction therapy. A bone marrow biopsy at 5 yearsrevealed less than 5% plasma cells, staining for both kappaand lambda light chains. At latest follow-up 13 yearsposttransplant, his creatinine was 1.5 and proteinuria wasstable at 0.38 gms/d. In the intervening years, he haddeveloped diabetes mellitus, hypertension, and hyperlip-idemia, and was on a range of medications, but withoutevidence of recurrence of myeloma.

I want to thank Dr. Cynthia Nast for inviting me toprovide this case and participate in this CPC, Dr. Jeffersonfor moderating the session, and Dr. Singh for his elegantdiscussion.

DisclosuresNone

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Published online ahead of print. Publication date available atwww.cjasn.org.

2728 Clinical Journal of the American Society of Nephrology