peter l. golding · patients with renal tubular acidosis excreted exces-sive amounts of ammonia at...

Postgraduate Medical Journal (August 1975) 51, 550-556.

Renal tubular acidosis in chronic liver disease

PETER L. GOLDINGM.B., B.S., M.R.C.P.

Royal Portsmouth Hospital, Portsmouth, Hants

SummaryRenal tubular acidosis of the gradient or classic type,thought to be due to a disorder of the distal tubule, hasbeen found to occur in 32% of 117 patients withchronic liver disease. Whilst the cause of this disorderis probably multifactorial, immunological mechanismsare considered to play a major role. The presence ofthis disorder might well be a cause, rather than theresult of, the various electrolyte abnormalities seen inpatients with chronic liver disease.

RENAL tubular acidosis (RTA) is a disorder of func-tion in which the renal tubule is unable to acidifyurine normally out of proportion to any reductionin the glomerular filtration rate. In a review byMorris in 1969 he reclassified and summarized themain features of two major types of tubular defect.In one there is an abnormality of the proximaltubular function in which there is a rate defect in theacidification process for the proximal tubule andmore than 15% of the filtered bicarbonate load isexcreted and the THCO3- is at or near its maximumat normal plasma bicarbonate concentration. Thistype characteristically occurs as one of several proxi-mal tubular dysfunctions but may appear as an iso-lated defect. This is referred to as bicarbonate wastingRTA or rate RTA. The other type of tubular defectis where the distal tubule is unable to maintain thesteep lumen peritubular hydrogen ion gradient andthis has been referred to as classic or gradient RTA.This latter condition is found in association withmany other diseases and abnormal metabolic states,as shown in Table 1. Of particular interest in thistable is that RTA is sometimes found in associationwith hypergammaglobulinaemic states and also inconditions where there is hyponatraemia or hypo-kalaemia. These disorders are commonly to be foundin patients with chronic liver disease and have beensuggested as aetiological agents in the sporadic casesof renal tubular acidosis reported in association withliver disease (Morris and Fudenberg, 1967; Read,Sherlock and Harrison, 1963; Seedat and Raine,1965; Leeson and Fourman, 1967; Shear, Bonkow-sky and Gabuzda, 1969). To determine the preva-lence and nature of the tubular defect in patients with

TABLE 1. Causes of Renal Tubular Acidosis (RTA)-gradient RTA; distal tubule

PrimarySporadicGenetically transmitted

Genetically transmitted systemic diseasesGalactosaemiaHereditary fructose intoleranceEhlers-Danlos syndrome

Metabolic disordersHyperthyroidism with nephrocalcinosisPrimary hyperparathyroidism

Hypergammaglobulinaemic statesMedullary sponge kidneyDrug

Amphotericin, vitamin D-induced nephrocalcinosisPyelonephritis (?)Renal transplantationElectrolyte imbalance

HyponatraemiaMassive diureticsHypokalaemia

chronic liver disease a systematic study was under-taken and the earlier results of this were reportedwhen it was shown that the distal or gradient type ofrenal tubular acidosis occurred commonly in patientswith primary biliary cirrhosis, active chronic hepa-titis and cryptogenic cirrhosis (Golding and Mason,1971). This report is an extension of the previousstudy.

Patients and methodsOne hundred and seventeen patients attending

Southampton General Hospital, The London Hos-pital, St Bartholomew's Hospital and King's CollegeHospital, were studied for tubular defects. Distaltubular acidification defects can occur in two ways,either presenting as an overt acidosis in which thepatient has a metabolic acidosis but is unable toacidify the urine, or as an incomplete variety wherethe tubular defect can only be demonstrated whenthe patient is given an acid load. Overt renal tubularacidosis was diagnosed in those patients who had ametabolic acidosis and whose urine pH was 6 orgreater. Under these conditions it was consideredunnecessary to give them a further acid loadingstress. To detect the incomplete variety, the acid

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Renal tubular acidosis in chronic liver disease 551

loading test of Wrong and Davies (1959) was used.The patient was given an ammonium chloride loadand the urine was collected over 2 hr periods for 8 hr.Each aliquot was analysed for urinary pH, titratableacidity and total ammonia excretion. In a normalindividual the urine pH falls to < 5 2 during thetest, the titratable acidity rises to > 24 [LEq/minand the ammonia excretion can be in excess of 33piEq/min. After studying a number of cases with thismethod the longer test of calcium chloride loadingwas preferred. In this test each patient receivedchloride 150 mEq/day for 3 days, thereafter the urinewas tested for urinary pH, titratable acidity andammonia excretion. All diuretics were stopped atleast 5 days before any acid loading test and hypo-kalaemia was corrected with oral potassium beforeany test was performed. Urinary amino acids weredetected by two dimensional paper chromatography,plasma copper levels were measured on an atomicabsorption spectrometer, the normal range being70-150 tig/100 ml. Autoantibodies were detected byan immunofluorescent technique using a 1 :10dilution of the patient's serum. Serum immunoglobu-lins were measured quantitatively by the singleradial immunodiffusion method on an immunoplateusing standard supply by the manufacturer (BaxterThetford).

ResultsThe incidence of renal tubular acidosis occurring

in the four diagnostic groups comprising the 117patients studied is shown in Table 2. The highestincidence of the incomplete type of renal tubularacidosis was found in those with primary biliarycirrhosis and active chronic hepatitis. Similarly theincidence of overt acidosis was also highest in thesetwo groups. Only one patient with alcoholic cirrhosiswas found to have an incomplete type of renal tubu-lar acidosis. In all, thirty-eight patients (32%) hadovert or incomplete tubular defect.

Patients with overt acidosis had symptoms of poly-dypsia, polyuria, muscular weakness, nausea andvomiting. In two cases these symptoms were respon-sible for the initial presentation in hospital beforeliver disease was diagnosed. In the other nine overtcases the tubular defect became apparent during thecourse of their liver disease. Hypokalaemia with aninappropriate loss of urinary potassium (44-105mEq in 24 hr) occurred in seven patients with overt

acidosis, whilst osteomalacia was seen in two cases.Proteinuria occurred in ten patients with either theincomplete or overt forms. The protein loss was notexcessive and did not exceed 2 g in 24 hr. Specifictests for tubular protein loss were not performed.Aminoaciduria was not seen in any patient andglycosuria was only noted in three patients withdiabetes. Nephrocalcinosis was seen in two patientsand in both of these urinary and plasma calciumswere normal (Fig. 1).

There was no correlation between the level ofglobulin in those with and those without the tubulardefect (Fig. 2), and likewise there was no differencein the globulin levels between those with overt andthose with incomplete acidosis. Similarly there wasno significant difference in the serum copper levelin those with and those without the defect (Fig. 3).

Qualitative changes in the pattern of acid excre-tion were noted in many patients with acidifyingdefects. Titratable acidity was below normal in allcases and the ammonia excretion accounted for anincreased percentage of total hydrogen ion excretion.Patients with renal tubular acidosis excreted exces-sive amounts of ammonia at a given urinary pH(Fig. 4). However, in those with overt acidosis anormal ammonia excretion for the urinary pH wasfound. In one patient, tested on admission to hospital,an incomplete type of distal tubular acidosis wasfound. She was excreting an excess of ammonia at120 Ftg/min at a urine pH of 5-7. Two months latershe developed a metabolic acidosis and the urine pHwas found to be 6-2. At this time her ammoniaexcretion was only 39 mEq/min. This apparent dropin ammonia excretion had occurred without anysignificant fall in the glomerular filtration rate.Creatinine clearance was measured in a large per-centage of the cases (Fig. 5) and was found to be ofthe same order in those with and those without renaltubular acidosis, although it tended to be lower inthose with the overt variety of the distal tubulardefect. It has been suggested that the increasedammonia excretion in patients with renal tubularacidosis is due to an increased creatinine clearance,however, as can be seen from Fig. 5, our findings donot confirm this.

Immunological studiesThe presence of mitochondrial, smooth muscle and

antinuclear antibodies, as well as the numbers of

TABLE 2. Renal tubular acidosis and chronic liver disease

No. Incomplete RTA Overt RTA Total abnormal (,')

Active chronic hepatitis 48 11 4 31Primary biliary cirrhosis 29 11 6 59Cryptogenic cirrhosis 25 4 1 20Alcoholic cirrhosis 15 1 0 7


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552 P. L. Golding

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FIG. 1. Straight X-ray of the abdomen in a patient with overt renal tubular acidosis showing nephrocalcinosis.

patients with abnormal levels of IgA, IgG and IgMare shown in Table 3. It can be seen that the presenceof renal tubular acidosis could not be significantlyassociated with abnormal levels, class of immuno-globulin, nor with any particular autoantibody.Renal histology was obtained in eight patients

with renal tubular acidosis and revealed an inter-stitial nephritis in seven, characterized by collectionsof lymphocytes with some fibrosis throughout therenal cortex (Fig. 6). In two patients there was alsoa diffuse calcinosis. Glomerular changes were mini-mal although in two other patients, one with overtrenal tubular acidosis and one with normal renalfunction, immunofluorescent techniques showedlinear staining of the basement membrane due toantibody deposition. This infiltration of the kidneysby lymphocytes could possibly indicate that cell-mediated immune mechanisms might be responsible

for the tissue damage and the tubular defect. Thiswas investigated using the leucocyte migration in-hibition test, details of which are described else-where (Mitchell et al., 1972; Smith et al., 1972;Soborg, 1968). Abnormalities of leucocyte migrationwere confined to those patients with renal tubularacidosis in the active chronic, primary biliary cir-rhosis and cryptogenic cirrhotic groups. No abnor-mality was found in patients with alcoholic cirrhosis.Of the twenty-one patients with renal tubular acido-sis tested, 62% were abnormal to renal antigens,whereas of thirty-four patients without the tubulardefect only 6% showed an abnormal migration. Ithas previously been shown that patients with thesetypes of liver disease have abnormal leucocyte migra-tion when using liver antigens (Smith et al., 1972)and it therefore could be argued that the inhibitionof migration, seen in patients with renal tubular


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FIG. 2. Serum globulin in chronic liver disease. (a) WithRTA; (b) without RTA. 0 = overt RTA.

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FIG. 3. Serum copper in chronic liver disease. (a) WithRTA; (b) without RTA. 0 = overt RTA.

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FIG. 4. Ammonia excretion in chronic liver disease. L, incomplete RTA; x, overt RTA; 0, normal tubular function.


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554 P. L. Golding

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FIG. 5. Creatinine clearance in chronic liver disease. (a)With RTA; (b) without RTA. 0 = overt RTA.

TABLE 3. Immunoglobulins, autoantibodies and RTA

RTA present RTA absent

IgA (% abnormal) 49 52IgG 45 55IgM 58 40Mitochondrial antibodies (0) 54 44Smooth muscle antibodies (0) 30 32Antinuclear factor 53 41

acidosis and autoimmune liver disease, could simplybe due to cross-reactivity. However, if one comparesthe reaction to renal antigens and liver antigens inthe same patients (Fig. 7), it can be seen that thereare four possible reactions. There are some that arenormal to both liver and kidney antigens, some thatare abnormal to liver but normal to renal antigens, a

third group who are normal to liver but abnormal torenal antigens and, finally, a group abnormal to bothantigens. In the latter group all the patients had renaltubular acidosis. This figure shows, therefore, thatcross-reactivity cannot be the whole answer to thisabnormal leucocyte migration.

DiscussionA defect of urinary acidification was found in 32%

of patients with chronic liver disease. This defect wasof the distal tubular or gradient type and presentedeither as an incomplete or an overt variety. It wouldappear that patients with the incomplete type are ableto maintain an acid base balance by excreting largerquantities of ammonium ion, but the reason for thisis unknown. It cannot be due solely to an abnormalcreatinine clearance. Anything which impairs am-monium excretion in these patients is likely, there-fore, to impair the excretion of total hydrogen ionthereby inducing an overt metabolic acidosis. Thefall in creatinine clearance could explain this in someof the overt cases, as shown in Fig. 5, but not in all.It is possible that the impaired ammonium excretioncould reflect greater damage, by some unknownmeans, to the distal renal tubule.

In potassium deficiency the ability of the kidneyto excrete a maximally acid urine is impaired butammonium excretion remains normal (Clark et al.,1955). Hypokalaemia was found in seven cases withovert acidosis though all of these had an inappro-priate loss of urinary potassium. However renaltubular acidosis itself is a known cause of hypo-kalaemia (Fourman and McCance, 1955). In thepatients with the incomplete variety, hypokalaemiahad only occurred at any time in twelve patients andall of these had been corrected with potassium sup-plements well before urinary testing. Thus, althoughit is possible that intracellular hypokalaemia mayhave existed, it could only account for a small num-ber of patients with tubular acidosis. A disturbanceof the peritubular circulation due to hyperglobulin-aemia has been suggested as a cause of renal tubularacidosis but there was no correlation between thelevel of the serum globulin and the presence of thedisorder thus confirming the findings of Morris andFudenberg (1967), Shearn and Tu (1968) and Tu etal. (1968). Leeson and Fourman (1967) suggestedthat in a patient with primary biliary cirrhosis andtubular acidosis a defect of acidification was due tothe deposition of copper in the renal tubules. How-ever, it is unlikely that an abnormality of coppermetabolism is a major factor in the development ofthe renal lesion in our patients. Muldowney, Freaneyand McGeeney (1968) found renal tubular acidosisin five cases of osteomalacia and suggested that therenal lesion might be due to a deficiency of vitamin Dcausing secondary hyperparathyroidism rather than


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Renal tubular acidosis in chronic liver disease 555

~~~4%7 g~~~~~~~~A.

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FIG. 6. Renal biopsy of patient with overt renal tubular acidosis showing lymphocyticinfiltration and tubular atrophy.

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FIG. 7. Comparison of leucocyte migration in the samepatients using liver antigen and kidney antigen. 0, Renaltubular acidosis.

a deficiency of vitamin D per se. Osteomalacia wasonly present in two of our cases and in neither ofthese did the tubular defect improve with adminis-tration of vitamin D over a prolonged period; fur-thermore the tubular lesion in these cases is usually aproximal lesion in which aminoaciduria and glycos-uria would be expected. In none of our cases was anyabnormal aminoaciduria found.

Increasing evidence points to an immunologicallesion as causing at least some cases of renal tubularacidosis (Carter, Whitworth and Mackay, 1971)and in this context an association between theSjbgren's syndrome and renal tubular acidosis is nowwell recorded (Shioji et al., 1970). In several suchpatients and in patients with renal tubular acidosis inassociation with other immunological disease, lym-phocytic infiltration of the renal cortex with tubulardestruction has been demonstrated (Pasternack andLinder, 1970; Kaltrieder and Talal, 1969; Tu et al.,1968). In the present series, Sjogren's syndrome andrenal tubular acidosis occurred together in 270% ofthe patients. The result, with renal antigens, suggeststhat cell-mediated responses are involved in thepathogenesis of the tubular defect. It is perhapsrelevant here that renal tubular acidosis has beendescribed in renal transplant patients in whom cell-mediated responses were thought to be responsiblefor rejection episodes (Feldman and Lee, 1967).Furthermore, tubular lesions, in rabbits immunizedwith renal antigens, are associated with mononuclearcell infiltration of the kidney (Klassen, McCluskeyand Milogrom, 1971) similar to that seen in thesepatients with renal tubular acidosis. Overall, theassociation between renal tubular acidosis andchronic liver disease could be due to multiple factors.Electrolyte abnormalities in patients with liverdisease could explain a tubular defect in somepatients but immunological factors probably play amajor role.


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556 P. L. Golding

AcknowledgmentsI would like to thank Dr J. Bamforth, Dr A. Dawson, Dr

R. Williams and the Physicians of the London Hospital forpermission to study their cases and also Mr McLean ofthe Photographic Department, Royal Portsmouth Hospital,for producing the plates and figures.

ReferencesCARTER,N. G., WHITWORTH, J.A. & MACKAY, [.R. (1971)

Impaired urinary acidification, its incidence in diseaseswith autoimmune features. Australian and New ZealandJournal of Medicine, 1, 39.

CLARKE, E., EVANS, B.M., MACINTYRE, I. & MILNE, M.D.(1955) Acidosis in experimental electrolyte depletion.Clinical Science, 14, 421.

FELDMAN, J.D. & LEE, S. (1967) Renal homotransplantationin rats. 1. Allogenic recipients. Journal of ExperimentalMedicine, 126, 783.

FOURMAN, P. & MCCANCE, R.A. (1955) Tetany complicatingthe treatment of potassium deficiency in renal acidosis.Lancet, i, 329.

GOLDING, P.L. & MASON, A.S.M. (1971) Renal tubularacidosis and autoimmune liver disease. Gut, 12, 153.

KALTRIEDER, H.B. & TALAL, N. (1969) Impaired renalacidification in Sjdgren's Syndrome and related disorders.Arthritis and Rheumatism, 12, 538.

KLASSEN, J., MCCLUSKEY, R.T. & MILOGROM, F. (1971) Non-glomerular renal disease produced in rabbits by immuniza-tion with homologous kidney. American Journal of Path-ology, 63, 333.

LEESON, P.M. & FOURMAN, P. (1967) A disorder of coppermetabolism treated with penicillamine in a patient withprimary biliary cirrhosis and renal tubular acidosis.American Journal of Medicine, 43, 620.

MITCHELL, C.G., SMITH, M.G.M., GOLDING, P.L., EDDLE-STONE, A.L.W.F. & WILLIAMS, R. (1972) Evaluation ofleucocyte migration test as a measure of delayed hyper-sensitivity in man suppression of migration inhibition by

puromycin. Clinical and Experimental Immunology, 11,535.

MORRIS, R.C., JR (1969) Renal tubular acidosis. New EnglandJournal of Medicine, 281, 1405.

MORRIS, R.C. & FUDENBERG, H.H. (1967) Impaired renalacidification in patients with hypergammaglobulinaemia.Medicine (Baltimore), 45, 57.

MULDOWNEY, F.P., FREANEY, R. & MCGEENEY, D. (1968)Renal tubular acidosis and aminoaciduria in osteomalaciaof dietary or intestinal origin. Quarterly Journal of Medi-cine, 37, 517.

PASTERNACK, A. & LINDER, E. (1970) Renal tubular acidosis,an immunopathological study on four patients. Clinicaland Experimental Immunology, 7, 115.

READ, A.E., SHERLOCK, S. & HARRISON, C.V. (1963) Activejuvenile cirrhosis considered as part of a systemic diseaseand the effect of corticosteroid therapy. Gut, 4, 378.

SEEDAT, Y.K. & RAINE, E.R. (1965) Active chronic hepatitisassociated with renal tubular acidosis and successful preg-nancy. South African Medical Journal, 39, 595.

SHEAR, L., BONKOWSKY, H.L. & GABUZDA, C.J. (1969)Renal tubular acidosis in cirrhosis. New England Journal ofMedicine, 280, 1.

SHEARN, M.A. & Tu, W.H. (1968) Latent renal tubularacidosis in Sjogren's syndrome. Annals of RheumaticDiseases, 27, 27.

SHIOJI, R., FURUYAMA, T., ONODERA, S., SAITU, H., ITO, H.& SASAKI, Y. (1970) Sjogren's Syndrome and renal tubularacidosis. American Journal of Medicine, 48, 456.

SMITH, M.G.M., GOLDING, P.L., EDDLESTON, A.L.W.F.,MITCHELL, C.G., KEMP, A. & WILLIAMS, R. (1972) Cellmediated immune responses in chronic liver disease. BritishMedical Journal, 1, 572.

SOBORG, M. (1968) In vitro migration human peripheral leu-cocytes in cellular hypersensitivity. Acta medica scandi-navica, 184, 135.

Tu, W.H., SHEARN, M.A., LEE, J.C. & HOPPER, J. (1968)Interstitial nephritis in Sjogren's Syndrome. Annals ofInternal Medicine, 69, 1163.

WRONG, O.M. & DAVIES, H.E.F. (1959) The excretion of acidin renal disease. Quarterly Journal of Medicine, 28, 259.


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