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Kidney International, Vol. 21(1982), pp. 528—534 NEPHROLOGY FORUM

Glomeruloscierosis in reflux nephropathy

Principal discussant: RAMzI S. COTRAN

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts

penis, testes, and urethral meatus were normal. The prostate was of normal size. Editors The BUN was 14 mg/dl; creatinine, 1.3 mg/dl (creatinine clearance, 113 mI/mm); blood chemistries were normal; the blood glucose was 93 JORDANJ. COHEN mg/dl; and the complement profile was normal. Serum protein was 7.5 JOHN 1. HARRINGTON gIdI with 4.3 g/dl albumin. Urinalysis showed a pH of 5; a specific JEROME P.KASSIRER gravity of 1.015; 4+ protein, no cells, and no bacteria. Urine culture was sterile. The 24-hour urine protein excretion was 2.4 g. Editor Chest x-ray showed borderline cardiomegaly with clear lungs. An Managing intravenous pyelogram revealed bilateral coarse scarring with caliecta- CHERYL J. ZUSMAN sis. The right kidney was smaller than the left. There was moderate ureterectasia extending down to the ureterovesical junction. A voiding cystourethrogram revealed a large-capacity bladder; the patient had no MichaelReese Hospital and Medical Center urge to void after almost 500 ml of contrast material was instilled. Bilateral reflux was greater and persistent on the left and was intermit- University of Chicago, tent on the right. The left ureter was dilated and tortuous. A left Pritzker School of Medicine ureterocele and right bladder diverticulum were visualized. and A biopsy of the left kidney showed focal scarring with interstitial New England Medical Center fibrosis and chronic inflammation, tubular atrophy, and dilation. Of 12 glomeruli, 4 were totally sclerosed, 4 showed segmental sclerosis, and 4 Tufts University School of Medicine had mesangial thickening with some periglomerular fibrosis. Immuno- fluorescent studies revealed 2+ to 3+ focal, mesangial, and peripheral capillary loop deposition of 1gM and C3, 1 + deposition of IgG, and no Case presentation IgA. Electron microscopy disclosed extensive loss of epithelial cell foot A 32-year-old man was admitted to the Beth Israel Hospital forprocesses and occasional poorly defined mesangial electron-dense evaluation of heavy proteinuria. At age 3 years the patient was admitted deposits. to another hospital with acute urinary retention. A diverticulum of the Bilateral ureteral reimplantation was performed by the Glenn-Ander- urinary bladder, locatedjust above the left ureteral orifice, was excised. son advancement technique. The urinary diverticulum was excised. A Postoperatively he developed a pelvic abscess that was treated success- cystogram done 2 months postoperatively showed no reflux. Five fully by drainage and antibiotic therapy. Three months after surgery the months after surgery the patient was asymptomatic except for lower child had no urinary tract symptoms, but a cystogram showed bilateral bilateral flank tenderness on palpation. Blood pressure was 130/80 mm reflux that was worse on the left. Three urinalyses in the first year after Hg; serum creatinine was 1.3 mg/dl, the urine culture was sterile, and surgery showed occasional white blood cells and a trace of protein. In the 24-hr urine protein excretion was 3.2 g. Thirteen months after his growing years he had recurrent episodes of tonsillitis. Although he surgery his renal function remained normal but proteinuria persisted occasionally had an aching pain localized in his left flank, he had no (2.5 g/24 hours). signs or symptoms of urinary tract infection. At age 18 years, he was found to have proteinuria during routine evaluation for military service. Discussion An intravenous pyelogram performed at that time was said to be abnormal, but no other studies were done. Six months prior to DR. RAMZI S. COTRAN(F.B. Mallory Professor of Patholo- admission, he was found to have a slightly elevated blood pressure (140/ gy, Harvard Medical School, and Chairman, Department of 90 mm Hg), and the 24-hour urine protein excretion was 2.8 g. Pathology, Brigham and Women's Hospital, Boston, Mass.): On admission to the hospital he complained only of occasional left This patient illustrates the recently discovered association flank pain. He denied heavy analgesic intake, skin infections, or gross chronictubulointerstitial hematuria. There was no family history of renal disease. The blood between glomerular proteinuria and pressure was 135/85 mm Hg; pulse, 72; and weight, 198 lbs. The ears disease, particularly reflux nephropathy and chronic pyelone- were noted to be large and slightly misshaped. Funduscopic examina- phritis. At age 32, he manifested significant asymptomatic tion showed minimal arterial narrowing, sharp discs, and no hemor- proteinuria and was found to have bilateral vesicoureteral rhages or exudates. The lungs and heart were normal and no hepato- reflux (VUR). In addition, he had coarse renal scarring and splenomegaly was evident. There was no costovertebral tenderness; calyceal deformity, both of which are typical of the lesions of chronic "atrophic" pyelonephritis. Presentation of the Forum is made possible by grants from Smith Kline & French Laboratories, CIBA Pharmaceutical Company, Renal scarring and VUR GEIGY Pharmaceuticals, and Boehringer Ingeiheim Ltd. Although the details of the patient's clinical history as a 0085-2538/81/0021-0528 $01.40 young child are not available, we can assume from what we © 1982 by the International Society of Nephrology know of the natural history of reflux nephropathy [1—3] that the

528 Nephrology Forum 529 patient's major scar formation occurred in childhood, probably Proteinuria and glomeruloscierosis around the time that the bladder diverticulum was excised. Paraureteral diverticula are known to be associated with VURClinicopathologic associations [4], and a cystogram performed in this patient 3 months after Following an asymptomatic childhood and young adulthood, operation showed bilateral VUR. No information is availablethe discovery of proteinuria was sufficient to exclude this regarding the presence of renal scars at that time, but inpatient from military service at age 18. An intravenous pyelo- children with VUR who develop renal scars, scarring is com-gram performed at that time was said to be abnormal. By age monly evident at the initial radiologic investigation, which is32, the patient had mild hypertension and significant protein- usually performed because of concomitant urinary tract infec-uria; radiographic studies showed reflux nephropathy with tion [3, 5]. For example, Rolleston, Shannon, and Utley foundpersistent bilateral VUR. Although the creatinine clearance was that 29 of 49 children with gross VUR in infancy already hadnormal, a renal biopsy revealed significant glomerular and scarred kidneys by the time they reached 12 months of age [1],interstitial damage. There was segmental and focal glomerulo- and Bailey noted that 10 infants with urinary tract infection andsclerosis, with total sclerosis of at least one-third of the VUR already had evidence of renal scarring at ages less than 7glomeruli. weeks [2]. In the few instances in which scars developed in Although one can argue that the glomerulosclerosis and the previously normal kidneys, the scarring occurred mainly beforereflux nephropathy were coincidental, recent studies suggest a the age of 5 years and almost invariably when urinary tractsignificant and prognostically important association between infection also was present [5]. It must be emphasized, however,the two conditions. Glomerular alterations including ischemic that in many children with VUR, scarring never develops, Inchanges, glomerular obsolescence, proliferation, and exudation fact, long-term follow-up discloses that VUR disappears eitherhave long been known to occur in the kidneys of patients with spontaneously or with antibacterial therapy in up to 80% ofchronic pyelonephritis and have been ascribed either to associ- instances [3]. Severe reflux and refiux associated with scarringated hypertension or uremia (sometimes called an "alterative" are the least likely to disappear, however, accounting for theglomerulitis) [12—14]. In addition, earlier studies had reported high frequency of scarring in adults with VUR (94%) [6]. heavy proteinuria in patients with chronic pyelonephritis, but in What determines this sequence of events in refiux nephrop-some instances the proteinuria was present without histologic athy? Hodson and associates have produced a model of surgi-confirmation of glomerular lesions; in other instances criteria cally induced VUR in piglets [7]; using this model, Ransley and for the diagnosis of chronic pyelonephritis were equivocal [15]. Risdon found that three conditions are required for scarring to In 1973, Zimmerman, Uehling, and Burkholder described occur: (1) bacterial infection, (2) vesicoureteral reflux; and (3)focal sclerosing glomerulopathy and proteinuria (in excess of intrarenal refiux [8]. These investigators observed that intrare-1.5 glday) in 8 patients with renal failure and VUR [16]. nal reflux in the multipapillary kidneys of young pigs occurredKincaid-Smith, however, was the first to draw attention to the only in renal papillae that had particular morphologic character-association of chronic pyelonephritic scarring with proteinuria istics [9, 10]. In contrast to the usual conical nonrefluxingand glomerulosclerosis [17—19]. She noted that protein excre- papillae, in which the papillary ducts opened onto a convextions greater than 0.2 g/day were present in 19 of 55 adults with surface via slit-like orifices, potentially refluxing papillae wererefiux nephropathy, and that proteinuria was the best guide to larger, had concave rather than convex tips, and containedprognosis. Thus, all but one of 11 patients whose renal function papillary ducts that opened into the calyx with gaping orifices.subsequently declined had significant proteinuria (mean, 2.36 Concave, potentially refluxing papillae are present in normalg/day), whereas all patients whose serum creatinine levels pigs, mostly in the upper and lower poles. More importantly,remained stable had either no proteinuria or less than 1 g in 24 these investigators detected similar concave papillae in thehours [19]. When renal tissue was obtained from patients with kidneys of infants and children dying of nonrenal causes. Theprotein excretions exceeding 0.2 g!day, 78% of the specimens authors found that two-thirds of all human kidneys contain atshowed focal and segmental hyalinosis and sclerosis [18]. These least one potentially refluxing papilla, and that in one-fifth of alllesions were universal in patients with a serum creatinine over human kidneys, 30% or more of papillae are concave. On the2.5 mg!dl [17]. basis of these findings, Ransley and Risdon proposed the "big- Several other studies subsequently reported focal glomeru- bang" hypothesis to account for early damage in refluxlosclerosis in association with proteinuria in reflux nephropathy nephropathy [11]: in the presence of gross VUR, the first few[15, 20—22]. Bhathena et al found focal glomerulosclerosis in all episodes of clinical or subclinical urinary tract infection affect23 patients who had received renal transplants for end-stage the concave, potentially refluxing papillae, leaving nonrefluxingreflux nephropathy; in these patients urinary protein excretion structures intact. The normal kidney parenchyma, drained byranged from 1.2 to 5.8 g/day [21]. Senekjian et al, in a study of 5 the nonrefluxing papillae, resists damage from both infectionpatients followed for 3 to 9 years, found progressive, irrevers- and VUR. It is possible that when infection occurs, the mor-ible renal failure following surgical correction of VUR [22]. phology of some apparently nonrefluxing papillae may beSurgery had been performed in these patients when renal modified and thus permit intrarenal refiux and new scar forma-function was already compromised; initial creatinine clearances tion in these previously unaffected areas, but this occurrence iswere 23 to 53 mI/mm at the time of operation. The patients thought to be unusual. This proposed mechanism could explainremained normotensive, either spontaneously or on therapy, how renal scarring proceeded in this patient despite an absenceand they were free of urinary tract infection, but all 5 developed of signs or symptoms of infection after the initial episode at ageend-stage renal failure. Four of the 5 had substantial and 3. This long, silent history prior to diagnosis is not unusual inpersistent proteinuria, and a biopsy specimen from one patient refiux nephropathy first detected in adults [6]. showed focal glomerulosclerosis. 530 Glomerulosclerosis in reflux nephropathy

In a comprehensive study of 54 patients with refiux nephrop-coiled structure and spherical particles thought to represent athy, Torres et al assessed renal function, protein excretion,altered bacterial forms [181, bacterial antigen has not been and glomerular histology and found that the clinical progressionlocalized in glomeruli of patients with chronic pyelonephritis to end-stage renal disease was not appreciably altered by [26, 27]. surgical correction of reflux in its advanced stages [15]. In Two possible autologous renal antigens are brush-border— addition, all of their patients with progressive renal disease hadrelated antigen and Tamm-Horsfall protein. The former is an significant proteinuria. The renal biopsy showed mesangialunlikely candidate for an auto-antigen, because the lesion hypercellularity and increased mesangial matrix; the patientsassociated with brush-border-antigen—induced glomerulone- with proteinuria also had a prominent focal and segmentalphritis is membranous nephropathy, not focal sclerosis. Tamm- glomerulosclerosis. Horsfall protein, however, is a possible endogenous antigen. Dr. Belicza, Flier, and I recently performed a retrospectiveThis substance, a urinary glycoprotein localized largely to casts clinicopathologic study of 51 patients whose kidneys wereand epithelial cells in the distal tubule [28], gains access to the removed surgically for chronic pyelonephritis associated withrenal interstitium in both human [291 and experimental [30] VUR or obstruction (unpublished data). In the extensivelyrefiux nephropathy. Elevated titers of serum antibody to sampled kidneys from these patients, lesions of segmental andTamm-Horsfall protein are found in patients with acute pyelo- focal glomerulosclerosis were found in 14 cases (28%). One-halfnephritis and reflux nephropathy, although the levels appear to of those with focal glomerulosclerosis had radiologic or mor-be diminished in patients with chronic disease [31]. Because phologic evidence of bilateral renal disease and a serum creati-macromolecules can move from the mesangium to the macula nine of over 2.5 mgldl. Sixty-three percent had 24-hour urinarydensa of distal tubules [32], it is at least theoretically possible protein excretions greater than 1 g/day, and 25% had excretionsthat Tamm-Horsfall protein could gain access in a retrograde greater than 3 glday. In contrast, with few exceptions, patientsfashion to the mesangium during obstruction or reflux, and without focal sclerosis had normal serum creatinine levels,elicit a local immune-complex reaction. Thus far, however, we minimal proteinuria, and unilateral disease. and others have failed to localize Tamm-Horsfall protein in the It is clear, therefore, that focal and segmental glomeruloscler-mesangium of these patients [21]. osis develops in some patients with refiux nephropathy and Macromolecular trapping and mesangial dysfunction. An chronic pyelonephritis and that, particularly in patients withalternative explanation for the deposition of 1gM and C3 is that bilateral disease, it is associated with significant proteinuria andmacromolecules are trapped as a result of mesangial "dysfunc- progressive renal damage. These findings suggest that thetion" [32, 33]. Although mesangial function and transport have glomerular lesion might be an important cause of deteriorationnot been studied in VUR, Raij et al found that they deviated of renal function in patients with VUR, particularly whenfrom normal in rats with ureteral obstruction [34], These neither hypertension, nor recurrent infection, nor obstructionauthors found increased mesangial accumulation of radiola- can explain the worsening of renal function. beled, aggregated IgG in obstructed kidneys; this accumulation appeared to be caused by a blockade of the efferent limb, which Pat ho genesis of glomerulosclerosis and proteinuria removes macromolecules from the mesangium. The mechanisms by which proteinuria and glomerulosciero- If trapping leads to deposition of macromolecules in glomeru- sis develop in patients with reflux nephropathy are subjects ofli, the reasons for predominant deposition of 1gM and C3 are not current investigation. Whereas some of the protein excretedclear. Velosa, Miller, and Michael found fixation of heterolo- may be "tubular" in origin [23], increased glomerular perme-gous complement in hyalinizing glomeruli of kidneys with ability is the major cause of excessive protein loss: more thanchronic pyelonephritis as well as early components of comple- 60% of the protein excreted is albumin, and electron microsco-ment and properdin; these findings suggest activation of both py of glomeruli shows loss of foot processes and other visceralclassic and alternate complement pathways [35]. In view of the epithelial changes characteristic of glomerular proteinuria.marked biochemical heterogeneity of the mesangial matrix—it Glomerular proteinuria was well documented in the patientcontains laminin, fibronectin, collagen, and glycosaminogly- under discussion today. At least four mechanisms might becans—C3 and 1gM deposition might conceivably represent involved in the genesis of these glomerular lesions: (1) immuno-interactions with components of the mesangial matrix and local logic injury; (2) macromolecular trapping and mesangial dys-specific activation of the alternate complement pathway. function; (3) vascular alterations and hypertension; and (4) Vascular alterations and hypertension. Although many of the glomerular hyperfiltration. I will discuss each of these, but Ireported patients with focal sclerosis and persistent proteinuria favor the last one. were hypertensive, it is unlikely that hypertension is the cause Immunologic injury. The presence of 1gM and C3 in theof focal sclerosis. Blood pressure often was only slightly sclerotic areas and mesangium of more than 50% of the patientselevated, and proteinuria sometimes preceded the hyperten- with focal sclerosis raises the possibility of an immune reaction. sion, the latter becoming manifest only after renal insufficiency The focal lesions could be caused by circulating or in-situdeveloped. In addition, focal glomeruloscierosis is not a promi- deposited immune complexes in which the antigen is a bacterialnent histologic feature of essential hypertension. product or an autologous tubular antigen. It seems unlikely that Vascular changes consisting of intimal hyperplasia and medi- bacterial antigens are involved; glomeruli are remarkably freeal hypertrophy are present to some degree in the majority of of immune complexes in the acute and healing phases of acutepatients reported to have focal sclerosis and reflux nephrop- pyelonephritis [24, 25], and focal sclerosis usually developsathy, but these changes often exist in the absence of hyperten- long after infection has disappeared. With the exception of asion [15].Thepathogenesis of these vascular alterations is simple electron microscopic demonstration in glomeruli of aunknown, and they might play a role in the development of Nephrology Forum 531

glomerulosclerosis, The point is that although hypertensionsevere glomerular lesions, and abundant proteinuria. Although clearly contributes to progressive renal failure in refluxhis creatinine clearance was normal, the biopsy showed total or nephropathy, it is not the main cause of proteinuria associatedpartial sclerosis of two-thirds of his glomeruli. It is likely that with focal sclerosis. his existing hyperfiltering glomeruli have maintained a normal Glomerular hyperfiltration. The final explanation is thatGFR, but that progressive sclerosis of remaining glomeruli will proteinuria and glomerulosclerosis result from heniodynamiceventually lead to a reduction of GFR. changes occurring in glomeruli adapting to reductions in renal Does the progressive glomeruloscierosis induced by adaptive mass. Proteinuria, glomeruloscierosis, and progressive azote-changes in remnant nephrons also occur in other renal disor- mia develop regularly in rats when renal mass is reducedders? Experimentally, focal glomerulosclerosis can be induced approximately 75% either by surgical resection or infarctionor accelerated in animals given puromycin aminonucleoside [36, 37]. The rapidity with which glomerulosclerosis developsfollowing unilateral nephrectomy [37]. In addition, evidence and the extent of lesions are proportional to the degree of renalsuggests that diabetic glomerulosclerosis is accelerated in ex- ablation [38]. Recent micropuncture studies performed in ratsperimental diabetes following removal of one kidney [40]. In one week following ablation of 90% of renal mass showed anhumans, proteinuria, glomerulosclerosis, or both have been approximately threefold increase of single-nephron glomerularreported as complications of analgesic-abuse nephropathy [41, filtration rate in remnant glomeruli over control glomeruli; this42], segmental hypoplasia (the Ask-Upmark kidney) [43], and increase was associated with elevations of both capillary plas-oligomeganephronia [44]. In the last condition, congenital renal ma flow and mean glomerular transcapillary hydraulic pressure hypoplasia reduces the number of glomeruli by more than one- difference [39]. At the same time, protein excretion by remnant half, but the remaining glomeruli undergo hypertrophy and the glomeruli was increased approximately twenty fold. Clearanceglomerular filtration rate increases, Patients with this disease studies using dextrans and horseradish peroxidases with vary-develop renal insufficiency at an early age because of progres- ing isoelectric points shnwed defects in both the size andsive glomeruloscierosis. Finally, the presence of a single kidney charge-selective properties of the glomerulus [38]. Morphologicsince childhood appears to predispose patients to the develop- studies showed endothelial and epithelial alterations as well asment of focal sclerosis, In a recent review of 586 renal patholo- increased deposition of 1gM in the mesangium and in scleroticgy specimens, Kiprov, Colvin, and McCluskey found unilateral foci of remnant glomeruli [381. In addition, deposition of tracerrenal agenesis in 5 of 29 patients with focal glomerulosclerosis; molecules (ferritin) in the mesangium was readily documented this incidence was greater than that anticipated by chance alone [38]. (P <0.0001)[45]. They also found focal glomerulosclerosis in 2 The contribution of hemodynamic changes to glomerularof 7 patients with unilateral renal agenesis (29%) among 9200 injury was shown in animals subjected to dietary proteinautopsies. By contrast, no glomerular disease was found in 10 restriction prior to renal ablation, For reasons that are not clear, patients who died 8 to 46 years after having unilateral nephrec- protein restriction obviates the increase in single-nephron GFR, tomy in adulthood, capillary plasma flow, and transcapillary hydraulic pressure that occurs after renal ablation. Animals treated in this way Surgery for reflux manifested much less proteinuria, and the charge-selective Is surgical correction of VUR indicated in this patient? The defect also was ameliorated; normal renal structure and perme-value of surgical treatment of VUR in general is now under ability to tracer molecules was maintained [39]. close scrutiny. Normand and Smellie have presented the case The basis for the adaptive hemodynamic alterations in thisfor conservative management with prophylactic antibacterial model is still unclear, as is the precise sequence of eventstherapy [461. They found no evidence that prognosis in children leading to increased glomerular permeability, mesangial alter- is improved by ureteral implantation, particularly in children ations, and glomeruloscierosis. With few exceptions, however,older than age 5. Surgical correction of reflux probably does not the clinical data presented earlier suggest that such a maladapt-prevent new scar formation. Whether persistent reflux in the ive response might be the cause of glomerulosclerosis andabsence of infection causes continuing renal damage is contro- progressive renal damage in reflux nephropathy. As notedversial. The experimental [7, 8] and clinical [28, 47, 481 evi- earlier, most of the patients with proteinuria, reflux nephrop-dence is conflicting. However, even those who believe that athy, and glomerulosclerosis had abnormal renal function or"sterile reflux" is harmful acknowledge that renal damage developed it shortly after proteinuria was discovered. In ouroccurs principally in high-pressure urinary tract obstructjon. series, daily protein excretion exceeding 1 g occurred mainly in These disorders, including posterior urethral valves and other patients with bilateral disease and focal sclerosis. In the seriescongenital obstructive lesions, lead to the "generalized or of Kincaid-Smith and Becker, only one of 14 patients withdiffuse" form of reflux nephropathy [49] rather than to the more unilateral VUR and reflux nephropathy had a protein excretiontypical, focal coarse scarring. With regard to prevention of greater than 0.2 g/day, whereas 18 of 37 patients with bilateral progressive glomerulosclerosis, in the studies reported thus far, reflux nephropathy had this degree of proteinuria [191. Al- surgery was performed for reflux after renal function already though glomerular lesions were present in patients with normal had begun to decline. In such cases, progression of renal renal function, the more advanced and widespread lesions insufficiency occurred despite surgical correction of the VUR. appeared in biopsies of patients with impaired renal function. In the series of Torres et al, the mean duration from the time of All the patients reported by Senekjian et al had creatinine diagnosis to the time end-stage renal failure developed was 79 clearances less than 50% of normal [221, and Torres et al noted a 13months for 11 surgically treated patients versus 86 11 similar correlation [15]. months for 16 untreated patients [15]. The patient under discus- The patient under discussion today had bilateral disease, sion today presented a particularly difficult problem in manage- 532 Glomerulosclerosis in reflux nephropathy ment, because his renal function was normal when the protein-past were thought to have so-called abacterial" chronic pyelo- uria was discovered. Perhaps we can consider the decision tonephritis. reimplant his ureters later in this discussion. DR. JOHN T. HARRINGTON: In the piglets with concave and convex papillae, has anyone shown whether concave papillae Questions and answers change with development, or do they always remain concave? DR. JEROME P. KASSIRER: Dr. Cotran, what is your hypothe- DR. COTRAN: In piglets I am not sure, but in humans sis to explain why only some patients with reflux nephropathyTamminen and Kaprio found no difference in the distribution of develop the focal sclerotic lesion? these types of papillae in kidneys of premature, young infants or DR. COTRAN: The data suggest that most, but by no meanschildren up to age 9.8 years [50]. From the other side of the all, patients who develop the lesion are the ones who havecoin, both Hodson and Ransley and Risdon agree that simple rather severe bilateral scarring. I suspect this is because it isnonrefluxing papillae may become refluxing from prolonged these patients' glomeruli that attain the hemodynamic alter-obstruction or adjacent inflammation. This explains the few ations sufficient to cause focal sclerosis. Once focal sclerosisrepeated instances of new scars developing in already scarred starts in some glomeruli, the lesions become progressive for thekidneys. But this does not happen very frequently. reasons discussed earlier. Hypertension is another poor prog- DR. HARRINOTON: If one transplants an isogeneic kidney into nostic sign in these patients. an animal that has had a five-sixths nephrectomy, does the DR. KASSIRER: Do you have any advice for clinicians wholesion in the remnant kidney reverse? follow patients with reflux? How can they prevent the lesions DR. COTRAN: People are looking at this question now in an from developing? attempt to discover the mechanism of the hemodynamic DR. COTRAN: The most important things are preventing initialchanges. scarring by treating infection early, and preventing further DR. CECIL H. COGGINS (Renal Unit, Massachusetts General reductions in kidney function by treating hypertension. Hospital, Boston, Mass.): Do you think this pathogenesis DR. KASSIRER: Do individuals who have had a kidney re-applies to other forms of focal sclerosis as well? moved and live for many years thereafter eventually develop DR. COTRAN: As I said earlier, patients with other forms of focal sclerosis? reduction in renal mass also develop focal sclerosis, but this is, DR. COTRAN: As I stated earlier, Kiprov, Colvin, andof course, indirect evidence. There are some people who McCluskey examined 9200 consecutive autopsies at the Massa- believe—Brenner and colleagues being the main proponents— chusetts General Hospital and found 10 adults who had under-that examples of progressive sclerosis may be due to hyperfil- gone remote nephrectomy. None of these developed focaltration [51]. There is, as you know, evidence for hyperfiltration sclerosis. The data from transplant registries show no evidencein diabetes [52]. We recently examined the kidneys from a that kidney donors fare worse than the control population. Dr.patient who had diabetes and unilateral renal artery stenosis; Kiprov is here—he might have additional comments. the kidney with renal artery stenosis had much less diabetic DR. D0BRI KIPR0v (Department of linmunopathology, Mas-glomeruloscierosis. There is a similar case in the literature with sachusetts General Hospital, Boston, Mass.): The availablea unilateral Kimmelstiel-Wilson lesion [53]. data are insufficient to prove that patients with adult unilateral DR. KASSIRER: Dr. Steinman, maybe you could elaborate on nephrectomy do not develop focal sclerosis. However, none ofthe rationale for correcting the reflux surgically in the patient our 10 patients with adult unilateral nephrectomy developeddiscussed today. The evidence sounds unconvincing that such any glomerular disease. These patients had lived with a singletreatment is likely to be beneficial. kidney between 8 and 46 years. DR. THEODORE STEINMAN (Director, Dialysis Unit, Beth DR. VIVIAN PINN (Assistant Professor of Pathology, TuftsIsrael Hospital, Boston, Mass.): The best defense of our University School of Medicine): As you know, most patients decision to operate on the patient in question is that he had with chronic pyelonephritis have considerable damage to thenormal renal function but substantial proteinuria. While it is not interstitium and the tubules secondary to bacterial infection and known whether correcting influx in individuals with normal ischemic changes with peritubular capillary disruption. How renal function will protect against loss of kidney function over much of the progressive renal damage do you think can bethe course of years, it is well documented that correction of attributed to this progressive lesion and how much to thereflux in individuals who already have moderate to severe glomeruloscierosis? impairment of renal function does not prevent the inexorable DR. COTRAN: Most of the evidence suggests that followingcourse to end-stage renal disease. An intravenous pyelogram, the initial few episodes of bacterial pyelonephritis, which causeperformed one week after correction of the reflux, revealed the renal scarring, progressive renal disease leading to end-stagepersistence of significant reflux and of pelvocalyceal dilation renal failure is not usually caused by persistent or recurrentwith a large postvoid residual. In contrast, a repeat study renal infection. There is little evidence that persistent renal performed 13 months later revealed a diminution in the pelvoca- infection per se causes these kidneys to continue to deteriorate. lyceal dilation, a return of the ureters to normal caliber, and In end-stage chronic pyelonephritis or reflux nephropathy, marked improvement in the postvoid residual. Significant corti- 100% of the kidneys have some glomerular scarring—eithercal scarring, noted on his original films, was not changed over total hyalinization, focal sclerosis, or both. This issue was wellthe initial 13 months of observation. More importantly, his studied by Bhathena et al [21]. Progression in chronic pyelone-kidney function continued to be normal 13 months later, but phritis appears to result from hypertension, focal glomerulo-heavy proteinuria persisted (2.5 g/24 hours). Most patients with sclerosis, or both. Some patients, of course, also have obstruc- similar degrees of proteinuria and severity of focal sclerosis do tion or stones. I think this scenario explains patients who in the progress to renal failure, albeit over a long time. A much longer Nephrology Forum 533 followup is necessary therefore before any statement can behemodynamic changes, from developing the same lesion? This made whether correction of the reflux was an appropriateought to occur, unless one postulates that the patients with procedure for this patient and is indicated in other similarlipoid nephrosis happen not to filter some compound that patients. We plan to repeat his kidney biopsy in the future andpatients with refiux nephropathy or partially nephrectomized compare the results with the original pathologic study. animals do. DR. KASSIRER: Of course, if he does not develop focal DR. COTRAN:Patientswith lipoid nephrosis may or may not sclerosis you will never know whether he might not havehave some hyperfiltration, but they have a lot of proteinuria. developed it without reimplantation. Clearly, you have im-Most of the protein leaks into Bowman's space. My guess—and proved his reflux but I doubt that you will be able to draw any this is only speculation—is that in human lipoid nephrosis there conclusions about subsequent glomerular disease. is diffusely leaky capillary wall without much necrosis of DR. ANDREW LEVEY (RenalDivision,NEMC): Anotherendothelial or epithelial cells. The "selective" protein lost from example of glomerular changes in interstitial disease is thethe circulation ends up in the urinary space and very little occasional appearance of heavy proteinuria and nephrotic syn-accumulates in the mesangium. In conditions that lead to focal drome in patients with allergic interstitial nephritis followingsclerosis, such as hyperfiltration or hyperfiltration superim- treatment with nonsteroidal antiinflammatory agents [54, 55].posed on an increased permeability (as occurs in the aminonu- Does your hypothesis explain the glomerular lesions in thesecleoside model with unilateral nephrectomy), there is also patients? cellular injury, and some larger proteins (including fibrin- DR. COTRAN: I don't think so. This association has beenrelated proteins) accumulate in the mesangium [331.Theprecise reported also with drugs other than nonsteroidal antiinflamma-mechanism by which this leads to progressive sclerosis is tory agents, for example, ampicillin [56]. Most of these patientsunknown but is now being studied in a number of laboratories have a low GFR. The renal lesion is one of minimal change[32]. disease with extensive loss of foot processes, and I don't Acknowledgments remember any of the patients having focal sclerosis. I think that the association in these cases may be due to the fact that both Dr. Theodore Steinman and Dr. Seymour Rosen, Beth Israel Hospi- minimal change disease and acute interstitial nephritis are tal, Boston, provided the case material for this discussion. immune-mediated in some way, but this is only speculation. Reprint requests to Dr. R. Cotran, Department of Pathology, DR. HARRINGTON:Inpatients with interstitial nephritis dueBrigham andWomen'sHospital, 75 Francis Street, Boston, Massachu- to nonsteroidal antiinflammatory agents, although the overallsetts 02115, USA GFR is reduced, you could still argue that single-nephron GFR References might be increased. Are there any experimental models of I. ROLLESTON GL, SHANNON FT, UTLEY WI: Follow-up of vesico- interstitial nephritis secondary to nonsteroidal antiinflamma- ureteral reflux. Kidney In! 8:S59, 1975 tory agents in which one could test that hypothesis? 2. BAILEYRR:An overview of reflux nephropathy, in Reflux DR. COTRAN: To my knowledge there is no good model for Nephropathy, edited by HODSON CJ, KINcAID-SMITH P, New acute drug-induced interstitial nephritis. York, Masson Publishing USA Inc., 1979 DR. STEINMAN: It is known that patients with the idiopathic 3. SMELLIE JM, EDWARDS D, HUNTER N, NORMAND IC, PRESCOD N: Vesicoureteral reflux and renal scarring. Kidney In! 8:S65, 1975 nephrotic syndrome who have a pathologic picture of focal 4. KING LR, SyRIAN NA, WENDEL RM, BURDEN JJ: Vesicoureteral sclerosis will have the initial lesion seen in the juxtamedullary reflux. JAMA 205:169, 1968 glomeruli. Are the juxtamedullary glomeruli the first areas of 5. SMELLIE JM, NORMAND ICS: Reflux nephropathy in childhood, in involvement in patients who have focal sclerosis as a conse- Reflux Nephropathy, edited by HODSON CJ, KINCAID-SMITH P, New York, Masson Publishing USA Inc., 1979 quence of reflux nephropathy? 6. KINCAID-SMITH P. BECKER G: Reflux nephropathy and chronic DR. C0TRAN: We could not detect a predominant juxtaglo- atrophic pyelonephritis. J Infect Dis 138:774, 1978 merular involvement in our study. 7. HODSON CJ, MALING TM, MCMANAMON PJ, LEWIS MJ: The DR. NICOLAOS MADIAS (Renal Division, NEMC): You men- pathogenesis of reflux nephropathy (chronic atrophic pyelonephri- tioned that rats with a remnant kidney on low-protein diets do tis). Br J Radio! 13(suppl):1, 1975 8. RANSLEY PG, RISDON RA: The pathogenesis of reflux nephrop- not develop an increase in single-nephron GFR and proteinuria. athy. Br J Radio! 14(suppl): 1, 1978 What happens to them in terms of survival? 9. RANSLEY PG: Intrarenal reflux: Anatomical dynamic and radiologi- DR. COTRAN: Others have shown long-term improved renal cal studies—Part I. Urol Res 5:61, 1977 function and survival in similar models with low-protein diets 10. RANSLEY PG, RISDON RA: The pathogenesis of reflux nephrop- athy. Cont rib Nephro! 16:90, 1979 [57]. 11. RANSLEY PG, RISDON RA: The renal papilla, intrarenat reflux, and DR.SERAFINO GARELLA (Divisionof Renal Diseases, Rhode chronic pyetonephritis, in Reflux Nephropathy, edited by HODSON IslandHospital, Providence, Rhode Island): According to the CJ, KINCAID-SMITH P, New York, Masson Publishing USA Inc., concepts you have expressed, the development of sclerosis 1979 seems related not to the hemodynamic changes found in experi- 12. 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