Renal function is commonly assessed by measurement of glomerular filtration rate (GFR). However, defects in tubular function may still exist in the presence of a normal GFR. In 12 patients with systemic lupus erythematosus (SLE), 6 of whom had previously been shown to have renal impairment, glomerular and tubular function were studied separately. In 4 patients, all parameters of renal function tested were normal. Impaired tubular function was found in 8 of the 12 patients, including 5 with normal GFR. Defects were noted in the ability to acidify urine in 7 patients and tubular reabsorption of phosphate was reduced in 2. A poor correlation was noted between the presence of renal tubular acidosis and the serum y-globulin level. The pathogenesis of the defect in urinary acidification in SLE and its prognostic significance are discussed.S. Afr. Med. J., 47, 132 (1973)

Eales, Lennox

Jessop, Susan

Mumford, Guillaim

Rabkin, Ralph

English

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132 S.A. MEDICAL JOURNAL 27 January 1973half an hour all our patients were well enough to beleft on their own.If no ischaemic changes following accidental intra-arterial injection are reported, and it can be shownthat the drug is not porphyrinogenic, it will becomea useful drug in the anaesthetist's armamentarium.In conclusion we have found Althesin to be an accept-able induction agent; but to be satisfactory as the soleanaesthetic in short procedures only when the larger doseis used.We wish to thank our medical and nursing colleagues inthe Department of Gynaecology for their co-operation; Pro-fessor A. B. Bull, Head of the Department of Anaesthetics,for his encouragement; and Professor G. G. Harrison for hishelp in the statistical analysis. We should also like to thankDr J. G. Burger, Medical Superintendent of Groote SchuurHospital, for permission to publish; and Glaxo-Allenburys(pty) Ltd, for supplying the drug.REFERENCESI. Selye, H. (1941): Proc. Soc. Exp. BioI. (N.Y.), 46, 116.2. Laubach, G. D., p'an, S. Y. and Rudel, H. W. (1955): Science, 122,78.3. Murpby, F. l., Guadagni, N. P. and Debon, F. (1955): l. Amer.Med. Assoc., 158, 1412.4. Gordon, G. S., Guadagni, N., Piccbi, J. and Adams, J. E. (1955):MM. et Hyg. (Geneve), 13, 251.5. Howland, W. S., Boyan, C. P. and Kuo-Chen Wang (1956): Anaes-thesiology, 17, I.6. Galley, A. H. and Lerman, L. H. (1959): Brit. Med. l., I, 332.7. Child, K. l., Currie, J. P., Davis, B., Dodds, M. G., Pearce, D. R.and Twissel, D. l. (1971): Brit. J. Anaesth., 43, 947.8. Campbell, 0., Forrester, A. C., Miller, D. C., Hutton, I., Kennedy,l. A., Lawrie, T. D. V., Lorimer, A. R. and McCall, D. (1971):Ibid., 43, 14.9. C1arke, R. S. l., Montgomery, S. l., Dundee, l. W. and Bovill, l. G ..(1971): Ibid., 43, 947.10. Bradford, E. M. W., Miller, D. C., Campbell, D. and Baird, W. L.(1971): Ibid., 43, 940,11. Savage, T. M., Foley, E. I., Coultas, R. l., Walton, B., Strunin, L.,Simpson, B. R. and Scon, D. F. (1971): Anaesthesia 26, 402.12. Swerdlow, M., Chakraborry, S. K. and Zahangir, M. A. H. M.(1971): Brit. l. Anaesth., 43, 1075.Renal Tubular Function in Systemic LupusErythematosus*SUSAN JESSOP, M.B. CH.B., RALPH RABKIN,t M.R.C.P. GLASG., GUlLLAIM MUMFORD, M.B. CH.B. ANDLENNOX EALES, M.D., F.R.C.P., Department of Medicine, University of Cape Town and Groote SchuurHospital, Cape TownSUMMARYRenal function is commonly assessed by measurement of910merular filtration rate (GFR). However, defects in tubu-lar function may still exist in the presence of a normalGFR. In 12 patients with systemic lupus erythematosus(SLE), 6 of whom had previously been shown to haverenal impairment, glomerular and tubular function werestudied separately. In 4 patients, all parameters of renalfunction tested were normal. Impaired tubular functionwas found in 8 of the 12 patients, including 5 with normalGFR. Defects were noted in the ability to acidify urine in7 patients and tubular reabsorption of phosphate wasreduced in 2. A poor correlation was noted between thepresence of renal tubular acidosis and the serum y-globu-lin level. The pathogenesis of the defect in urinary acidi-fication in SLE and its prognostic significance are dis-cussed.S. Afr. Med. l., 47, 132 (1973)."Date received: ID August 1972.tPresent address: Head of Renal Unit, Department of Medicine, Uni-versity of Witwatersrand. Johannesbur.2..Subclinical disorders of renal tubular function have beendescribed in a variety of hypergammaglobulinaemicconditions, including 'auto-immune' diseases such asSjogren's syndrome,'" systemic lupus erythematosus(SLE),3 alveolitis' and chronic active hepatitis.' Thereported abnormalities of renal tubular function includeimpairment of acid excretion and urinary concentration.It has been suggested tbat the hypergammaglobulinaemicstate may be causaUy related to the tubular dysfunction.The purpose of this investigation was to examine variousparameters of tubular and glomerular function in patientswith SLE, and to study the relationship between thedefects of renal function and the presence ofhypergammaglobulinaemia.PATIENTS AND METHODSTwelve patients (Table 1), 6 of whom were known tohave renal disease, were studied. There were 10 femalesand 2 males, aged between 19 and 61 years. AU conformedto Harvey's diagnostic criteria for SLE.· This permittedthe inclusion of a patient who had discoid lupus ery-thematosus; haemolytic anaemia, polyarthritis and27 Januarie 1973 S.-A. MEDIESE TYDSKRIF 133TABLE I. CLlNCAL FEATURESPatien:s123456789101112Estimated durationdisease (mon~hs)33624120818096360231011662Estimated durationrenal diseaseoooooo2011111550Other major manifestationsThrombocytopeniaPleurisyPneumonia, Raynaud's phenomenonPleurisyArthritisDiscoid LEDiscoid LE, anaemia, arthritisPneumoniaArthritis, pleurisyArthritisConvulsions, arthritisArthritis, adenopathyDrugsAmpicillinNonePrednisone 5 mgPrednisone 30 mgPrednisone 10 mgPrednisone 20 mgPrednisone 10 mgPrednisone 60 mgPrednisone 60 mgPrednisone 60 mgPrednisone 15 mgNoneCcr TRP OSM160 130 1300130 110 1100100 90 900•;0 70 700•••40 50 500 •• • •mls/mirvl'73m2 Percentage mOsm/kgFig. 1. Creatinine clearance (Ccr), tubular reabsorption ofphosphate (TRP) and maximum urinary osmolality(OSM) 8 hours after injection of pitressin. Shaded are3.§represent mean ± 2 SD of control values.was reduced in 2 patients, neither of whom showedevidence of hyperparathyroidism. Three patients wereunable to concentrate urine normally, as judged bythe maximal urine osmolality attained 6 - 8 hours afterthe administration of pitressin tannate in oil.The pattern of acid excretion in the presence ofsystemic acidosis, induced with ammonium chloride,is shown in Fig. 2. All 6 patients with clinical renaldisease had an impaired ability to lower urinary pH tonormal levels (normal range 4,68 - 5,19). In the 4 patientswho were unable to reduce pH below 5,40, TA productionwas decreased. Ammonium excretion was also decreasedin 2 of these patients, but was normal when correctedfor urine pH. The 1 patient with systemic acidosispresent before acid loading died subsequently fromprogressive renal failure. In 1 patient, who was ableCreatinine clearance was reduced in 3 patients (Fig. I),the lowest being 26 mllmini 1,73 m'. Urinary proteinexcretion was increased in 5 patients, 2 of whom hadthe nephrotic syndrome. Defects in tubular function werealso present (Fig. 1). Tubular reabsorption of phosphateRESULTSnephritis, but no LE cells. Fourteen healthy volunteers,aged 19 to 40 years, acted as controls.The protocol used during the investigation followedessentially that of the one-day renal function test ofEdwards et al.' This entailed the collection of a mid-stream urine specimen for microscopy and culture, 2arterial blood samples, and 2 3-hour timed urinespecimens, followed by a 2-hour urine collection.Parameters of renal function measured included thecreatinine clearance, phosphate clearance, proteinexcretion and the maximal urinary concentration attainedafter the subcutaneous injection of 5 units of pitressintannate in oil. In addition, the ability to handle anacid load was tested according to the short oral ammoniumchloride loading test of Wrong and Davies.8 Urine pH,titratable acid (TA), ammonium and bicarbonate weremeasured in the last 2 urine collections, and acid-basestudies were performed on arterial blood collected before,and during the test. Total hydrogen ion excretion wasestimated as the sum of TA and ammonium, minusbicarbonate.Activity of the immune process was assessed byestimation of total haemolytic complement. Urine pHwas measured at room temperature with a glass electrodepH meter. TA was determined according to the methodof Wrong aHd Davies," urinary ammonia by the micro-diffusion method of Conway; and urine bicarbonate bythe method of Van Slyke and Neill;'° employing theHenderson-Hasselbalch equation. Urea, creatinine andcalcium were measured with the Technicon auto-analyser.Urine osmolality was determined by means of an advancedosmometer. Serum proteins were analysed by paperelectrophoresis. Total haemolytic complement wasmeasured according to a modification of the methodof Kent et at. ll134 S.A. MEDICAL JOURNAL 27 January 1973pEq/min/H3m2DISCUSSIONbeing minimal in 2 cases. Of the 3 patients with lowcomplement levels and more severe defects, 2 havesubsequently died, 1 of renal failure. The other (whowas azotaemic and hypertensive) died at home, so thecause of death could not be established. The third patientis being maintained on chronic dialysis. Renal biopsieswere performed on 4 of the patients who were known tohave renal disease before entering this study, confirmingthe clinical diagnosis of lupus nephritis.Twelve patients with SLE were selected for this study.In 6, renal impairment had been demonstrated previously.At the time of the study, all parameters of renal functiontested were normal in 4 patients. Impaired tubularfunction was found in 8 of the 12 patients, including5 with normal glomerular filtration rates (GFR). Fiveof the 12 patients exhibited proteinuria; all had abnormaltubular function, while in only 3 was the GFR diminished.The reduced reabsorption of phosphate found in 2patients cannot be explained by parathyroid overactivity,or by a reduction in the GFR. In 1 patient, the defectcould have been secondary to prednisone treatment,.since it has been shown in dogs that corticosteroidsmay inhibit the tubular reabsorption of phosphate.%> TAproduction was reduced in 4 of the 6 patients whofailed to lower their urine pH to normal levels. Ammo-nium production was normal in these patients, whencorrected for urine pH. One patient showed low TAand ammonium excretion, but produced urine with apH in the normal range.Several immune disorders have been described inassociation with a renal tubular acidosis. These in-clude multiple myeloma," Sjogren's syndrome,"""hyperglobuIinaemic purpura," chronic active hepatitis'and SLE.' In all these conditions, except multiple myeloma,where a proximal renal tubular acidosis occurs, thetubular acidosis is of the distal variety. Distal renaltubular acidosis is characterized by a failure to produceurine of low pH. The tubules are unable to excretehydrogen ions against a concentration gradient. In thisTA NH. TotAc.180 2..'.5'.. I'. I'.50 •• 120•• 50 I.•,.3. •• •apHF~ 2. Lowest urinary pH, greatest amount of titratableacid (TA), ammonium (NIL), and total acid (Tot. Ac.)excreted after an acid load. Shaded areas represent mean± 2 SD of control values.to lower urine pH to 5,12, total hydrogen ion productionwas reduced as a result of impairment of excretion ofboth TA and ammonium.Glycosuria was found in 1 patient, who was knownto have diabetes mellitus, and who had no defect inrenal function. Urinary tract infection was detected in1 patient, who demonstrated a trivial defect in acidification.Total serum globulin was elevated in 7 patients and in3 of these impaired acid excretion was present (Table II).Serum y-globulins, however, were raised in only 2patients. Thus an inconstant relationship existed betweenrenal tubular acidosis and serum y-globulin levels. Alpha.-globulin was raised in the patient who demonstrated apattern of acid excretion similar to that found in chronicrenal failure.Total haemolytic complement was reduced in 7 patients(Table II), 2 of whom had no evidence of renal disease.The other 5 had defects in acidification, the disorderTABLE 11. SERUM PROTEINSGlobulins· Complement·Patient LE (g/100 ml) Gammaglobulins· (C'HSO u/ml) Tubular function1 + 2,2 1,6 46 Normal2 3,9 1,8 294 Normal3 I 3,3 1,6 161 NormalT4,3,3 ND 217 NormalT5 I 3,6 1,9 50 NormalT8 4,0 1,9 217 Defective7 2,5 1,4 217 Defective8 + 1,7 1,4 86 Defective9 + 3,7 2,6 0 Defective10 + 4,1 2,6 128 Defective11 + 2,5 1,4 109 Defective12 2,5 1,0 24 Defective• Normal: globulin: 1,5 - 3,0 g/l00 ml; gammaglobulin: 1,0 - 1,8 g/l00 ml; complement: 160 - 210 C'H50 u/mf.S.-A. MEDIESE TYD~I(jUF27 lanuarie 1973variety of renal tubular acidosis, TA excretion is impaired.In the complete form, which is associated with a basalsystemic acidosis, ammonium excretion is also reduced,but it is normal when corrected for urine pH. This wasseen in 1 of our patients (case 12), who subsequentlydied of progressive renal failure. At the time of thestudy, her creatinine clearance was 45 mljminj 1,73 m'and, in view of the report by Elkinton," that acidosisdoes not usually occur until glomerular filtration rateis below 20 mljmin, it is unlikely that her acidosis wasdue to generalized renal failure. In the incomplete varietyof renal tubular acidosis, found in 5 of our patients,no systemic acidosis occurs and ammonium production,when corrected for urine pH, is supranormal. Three ofthese patients with distal renal tubular acidosis exhibitedanother defect of distal tubular function, namely afailure to concentrate urine normally.In generalized renal failure, although urinary pH isusually low, total acid excretion is reduced as a resultof impaired ammonium excretion and, to a lesser extent.reduced TA excretion. The lowered TA production inpatients with generalized renal failure is secondary tothe reduced filtration of phosphate. One of our patients(case 10) exhibited this pattern of acid excretion, but hehad relatively good renal function as judged by the crea-tinine clearance of 82 mljmin/l,73 m'.As renal tubular acidosis may also be secondary tohyperparathyroidism, hypokalaemia, hypercalcaemia andpyelonephritis, each patient was screened for evidence ofthese conditions. In 2 patients with minimal defects inacidification and normal GFRs, the disorder may possiblyhave been secondary to a urinary tract infection inone, and hypokalaemia in the other.It has been suggested that the hypergammaglobulinaemiafound in 'auto-immune' diseases may be responsible forthe disturbance in acidification described in thesedisorders."" Impairment of acid excretion could bedue to reabsorption of filtered globulins by the tubularcells. Since the proximal tubule is the I!lajor site ofprotein reabsorption, one would expect a proximal tubularacidosis to occur. However, it is possible that globulinscould reach the distal tubular cells by leaking out ofperitubular capillaries, damaged by the immune process.In cases of multiple myeloma associated with theFanconi syndrome, protein-like inclusion bodies havebeen demonstrated in the proximal tubular cells.'" Inpatients with distal tubular acidosis, however, inclusionbodies have not been demonstrated in the distal tubules.The possibility that hypergammaglobulinaemia mayimpair circulation in the distal peritubular vessels eitherby increasing viscosity or by producing a vasculitis,has also been postulated.' However, no histologicalevidence of vascular damage has been noted.'" It hasbeen suggested" that there may be specific antibodies,reacting with tubular cells. In Sjogren's syndrome""'"where peritubular infiltrates of round cells are prominentin the kidney, immunoglobulin and complement depositshave been described in the tubular cells of patients withrenal tubular acidosis. However, different workers"''''have failed to detect immunoglobulins in tubular cellsof patients with hypergammaglobulinaemia due to othercauses.135The occurrence of renal tubular acidosis in the absenceof hypergammaglobulinaemia in many of our patients.leads us to believe that hypergammaglobulinaemia isnot the main factor producing this disturbance of renalfunction. This is in agreement with the work of Tu andShearn: who also studied a group of patients with SLE.However, Morris and Fudenberg" demonstrated a highincidence of renal mbular acidosis in patients withhypergammaglobulinaemia and Talal er al." foundsignificantly raised globulin levels in patients with renaltubular acidosis.It has been shown that a fall in serum complementin SLE may herald the onset of an active phase of thedisease."'» It is commonly associated with renal involve-ment and thus may be a guide to prognosis in SLE."In our study, the combination of low serum complementand renal tubular acidosis carried a particularly poorprognosis, as 2 patients died, and the third is requiringchronic dialysis.This work fonned part of the programme of the MRCjUCTRenal Metab{)lic Research Group which is supported by theUniversity of Cape Town and by the South African MedicalResearch Council.We wish to thank M. Levey, H. Page and R. Edelson forable technical assistance; Dr J. G. Burger, for facilitiesgranted; and Dr O. L. Meyers for the serum complementestimations.REFERENCES1. Shearn, M. A. and Tu, W. H. (1968): Ann. Rheum. Dis., 27, 27.2. Shioji, R., Furuyama, T., Onodera, S., Saito, H., Ilo, H. andSasaki, Y. (1970): Amer. J. Med., 48, 456.3. Tu, W. H. and Shearn. M. A. (1967): Ann. Intern. Med., 67, lOO.4. Mason, A. MS., McUlmurray, M. B., Golding, P. L. and Hughes.D. T. D. (1970): Brit. Med. J., 4, 596.5. Seedat, Y. K. and Raine, E. R. (1965): S. Afr. Med. J .• 39, 595.6. Harvey, A. M., Shulman, L. E., Tumulty, P. A., Conley, C. L.and Schoenrich, E. H. (1954): Medicine (Balt.), 33, 291.7. Edwards, K. D. G., Stewart, J. H., Asheley, B. C. E. and Whyte,H. M. (1964): Proceedings of the Australian Association of ClinicalBiochemislS, I, 101.8. Wrong, O. and Davies, H. E. P. (1959): Quart. J. Med., 28, 259.9. Conway, E. J. (1947): Micro-di//usion Analysis and VolumetricError. London: Crosby Lockwood.10. Van Slyke, D. D. and Neill, .T. M. (1924): J. Bio!. Chem., 61, 523.11. Kent, J. P., Bukantz, S. C. and Rein, C. R. (1946): J. Immun., 53,37.12. Roberts, K. E. and PitlS, R. F. (1953): Endocrinology, 52, 324.13. Constanza, D. J. and Smoller, M. (1963): Amer. J. Med., 34, 125.14. Talal. N., Zisman, E. and Schur, P. H. (1968): Arthritis Rheum.,11, 774.15. Mason, A. M. S. and Golding, P. L. (1970): Brit. Med. J., 3, 143.16. Elkinton, J. R. (1963): Med. Clin. N. Amer., 47, 935.17. Morris, R. C. and Fudenberg, H. H. (1967): Medicine (BaiL), 46,57.18. Engle, R. L. and Wall is. L. A. (1957): Amer. J. Med., 22, 5.19. Talal, N. (1971): Ann. Intern. Med., 74, 633.20. McCurdy, D. K., Cornwell, G. G. and De Pratti, V. J. (1967):Ibid., 67, 110.21. Wilson, D., William., R. C. and Tobian, L. (1967): Amer. J. Med.,43. 356.22. Schur, P. H. and Sandson. J. (1968): New Eng!. J. Med., 278, 533.23. fJ;I~Wns, R. C. and Law, D. H. (1958): J. Lab. C1in. Med., 52.24. Townes, A. S., Stewart, C. R. and Osier, A. G. (1963): Bull. John.Hopk. Ho,p., 112, 202.IIIIIIIIIIIIIIIIIIIIIIIIIIIII

Renal Tubular Function in Systemic Lupus Erythematosus

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Renal Tubular Function in Systemic Lupus Erythematosus

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