Fibrosing Alveolitis Associated with Renal Tubular Acidosis

The discovery of a case of renal tubular acidosis and fibrosing alveolitis led to the investigation of 19 further patients. Abnormal pulmonary function tests were found in a further four patients with overt renal tubular acidosis and in four out of eight patients with “incomplete” renal tubular acidosis. The response to an ammonium chloride test in seven patients with cryptogenic fibrosing alveolitis was normal. Those patients with a defect of both renal acidification and pulmonary gas transfer had concurrent autoimmune diseases such as Sjögren''s syndrome and primary biliary cirrhosis. It is suggested that the renal and pulmonary abnormalities may be part of a systemic disorder capable of affecting many organs. Moreover, hyperglobulinaemia and autoantibodies in these patients further suggests that immunological mechanisms are concerned in the pathogenesis of these abnormalities.     

Hereditary Nephropathy with Hematuria (Alport's Syndrome)

Among 82 members and four generations of a French-Canadian family, 14 cases of hereditary nephropathy (Alport''s syndrome) were documented. Five additional members of the family had died, probably because of this same illness. Deafness occurred in five family members with nephropathy and in one without renal disease. Ten of 12 affected males died in uremia before they had reached the age of 40 years. One of seven affected females died following a pregnancy. In two surviving patients, special investigations failed to elicit intrinsic tubular defects such as amino-aciduria, renal tubular acidosis, hyperphosphaturia or renal glucosuria. Systemic illness such as abnormal aminoacids in serum, primary hyperoxaluria, diabetes mellitus and infections were also excluded. Immunological defects were not demonstrable and the staining of renal biopsy tissue with fluorescein-labelled anti-β₁c, anti-IgG and antifibrinogen was negative. Renal tissue material of early, advanced and terminal hereditary nephropathy showed both tubular and interstitial, vascular and glomerular lesions. Electronmicroscopy showed marked thickening of tubular and glomerular basement membranes, increase of mesangial tissue and fusion of foot processes but failed to demonstrate “immune deposits.” It is postulated therefore that hereditary nephropathy results from an inborn error of metabolism where an as yet unidentified metabolite damages the renal tissue as well as the acoustic nerve, analogous perhaps to the action of certain drugs, e.g. nephro-ototoxic antibiotics.     

Purpura associated with hypergammaglobulinemia,renal tubular acidosis and osteomalacia.

Two patients with hyperglobulinemia associated with purpura were studied. One had features of Sjögren''s syndrome, while the other appeared to have a primary condition -- "chronic benign purpura". Both patients also had renal tubular acidosis, osteomalacia and renal calculi, with disturbed calcium metabolism and acid-base balance. Autoantibodies were detected in the serum of both patients, and mononuclear cell infiltrates were noted in skin and kidney biopsies from both.     

“Sicca Complex” in Liver Disease

Sixty-three patients with liver disease were studied for the presence of the components of Sjögren''s syndrome. The “sicca complex” (that is, patients without arthritis) was detected in 42% of patients with active chronic hepatitis, 72% with primary biliary cirrhosis, and 38% with cryptogenic cirrhosis. One patient with active chronic hepatitis and one with primary biliary cirrhosis had rheumatoid arthritis. No evidence of Sjögren''s syndrome was detected in seven patients with alcoholic cirrhosis. It is suggested that the sicca complex and autoimmune liver disease may be part of a systemic disorder in which immunological mechanisms are concerned in the pathogenesis.     

NONOBSTRUCTIVE OLIGURIA—Differential Diagnosis

A review is presented of ten years'' experience with the differential diagnosis of oliguria, utilizing the standard tests of renal function with the addition of the phenolsulfonphthalein excretion and urinary chloride measurements. The histories of 60 patients seen in consultation because of 24-hour urinary volume of less than 400 ml were studied in order to clarify the value of these tests. Particular attention was given to the postoperative “dilution state,” the oliguria of which tends to mimic that of “acute tubular necrosis.”In only 25 per cent of the 60 cases was “acute tubular necrosis” responsible for the oliguria. In the remaining 75 per cent of patients, oliguria was due either to the effects of simple dehydration without tubular damage, or to tubular dysfunction on a physiologic rather than an organic basis. Thus, three out of four patients with oliguria required aggressive and specific fluid-electrolyte therapy, often with the intensive use of potassium. One out of four required the opposite in therapy—controlled dehydration without added potassium and, on occasion, peritoneal or extracorporeal dialysis, in order to allow six to ten days for tubular repair.     

Renal tubular acidosis: developments in our understanding of the molecular basis

Renal tubular acidosis is a metabolic acidosis due to impaired acid excretion by the kidney. Hyperchloraemic acidosis with a normal anion gap and normal (or near normal) glomerular filtration rate, and in the absence of diarrhoea, defines this disorder. However, systemic acidosis is not always evident and renal tubular acidosis can present with hypokalaemia, medullary nephrocalcinosis and recurrent calcium phosphate stone disease, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. Renal dysfunction in renal tubular acidosis is not always confined to acid excretion and can be part of a more generalised renal tubule defect, as in the renal Fanconi syndrome. Isolated renal tubular acidosis is more usually acquired, due to drugs, autoimmune disease, post-obstructive uropathy or any cause of medullary nephrocalcinosis. Less commonly, it is inherited and may be associated with deafness, osteopetrosis or ocular abnormalities. The clinical classification of renal tubular acidosis has been correlated with our current physiological model of how the nephron excretes acid, and this has facilitated genetic studies that have identified mutations in several genes encoding acid and base ion transporters. In vitro functional studies of these mutant proteins in cell expression systems have helped to elucidate the molecular mechanisms underlying renal tubular acidosis, which ultimately may lead to new therapeutic options in what is still treatment only by giving an oral alkali.     

Histological Reassessment of Three Kidneys Originally Described by Richard Bright in 1827-36

Portions of kidney from three patients with renal disease that were originally described by Richard Bright between 1827 and 1836 have been preserved in the Gordon Museum at Guy''s Hospital. Histological study has shown that two cases fall into the current diagnostic category of mesangiocapillary (membranoproliferative) glomerulonephritis. One of these patients had a five-year clinical history and died with chronic renal failure and uraemia. The other patient died after three to four months with a severe nephrotic syndrome. The third patient was a young woman with chronic “phthisis pulmonalis” and renal amyloidosis.     

Metabolic Bone Disease Secondary to Renal and Intestinal Disorders

Metabolic bone disease occurring in renal or intestinal disorders has been reviewed with particular reference to etiological factors.Hyperparathyroidism is seen as a recurring cycle of renal damage—hyperphosphatemia—hypocalcemia—parathyroid stimulation—mobilization of bone calcium and phosphate—renal tubular phosphate rejection. In intestinal cases, the initial stimulus is presumably hypocalcemia.Osteomalacia is seen as resulting from phosphate depletion for the following reasons:1. Experimentally, rickets results from dietary phosphate restriction in rats.2. Such rickets is not prevented by the presence of normally adequate amounts of dietary vitamin D, and may therefore be termed “resistant” in the clinical sense.3. Osteomalacia or rickets in intestinal malabsorption and renal tubular disorders is associated with hypophosphatemia due to excessive fecal or urinary loss.4. Renal tubular rickets has been healed by oral phosphate loading in some studies.5. Acidosis may induce osteomalacic changes, experimentally and clinically (for example, in uretero-sigmoidostomy). Reversal of systemic acidosis with oral bicarbonate has resulted in phosphate retention and a rising serum phosphate in one such case.6. Preliminary data from analysis of full-thickness bone biopsy in two osteomalacic patients shows a significant reduction in calcium and phosphate content.7. Despite the hyperphosphatemia of azotemic renal failure, over-all phosphate depletion may be present in this situation also due to: • Diminished dietary phosphate in low protein diets • Nausea and vomiting • Occasional diarrhea • The use of oral phosphatebinding antacids • Perpetuation of urinary phosphate losses by reduction in proportion of tubular reabsorbed phosphate (secondary hyperparathyroidism) and possibly high filtered load per nephron • Repeated losses of phosphate to bath fluid during dialysis.     

Lymphocyte cytotoxicity for kidney cells in renal tubular acidosis of autoimmune liver disease.

Sensitisation to a renal tubular antigen, Tamm-Horsfall glycoprotein, has been shown to be common in patients with renal tubular acidosis complicating autoimmune liver disease, and it has been suggested that this immune reaction, by damaging renal tubular cells, might be responsible for the acidification defect. The lymphocytes from 10 out of 13 patients with chronic active hepatitis or primary biliary cirrhosis and an associated renal tubular acidosis were shown to be cytotoxic for a kidney cell line known to secrete Tamm-Horsfall glycoprotein. The cytotoxic reaction was blocked by this antigen, but not by two other proteins, indicating that sensitisation to the renal glycoprotein was the likely cause of the target cell damage. Significant reduction in cytotoxicity after the addition of aggregated IgG suggested that the reaction was of the antibody-dependent cell-mediated type. These results, together with the finding of antigenic material in the surface membrane of liver cells that cross reacts immunologically with Tamm-Horsfall glycoprotein, provide an explanation for the association between chronic liver disease and renal tubular dysfunction.     

Renal tubular acidosis--underrated problem?

Renal tubular acidosis (RTA) is a hyperchloremic metabolic acidosis characterized by a normal anion gap and normal (or near normal) glomerular filtration rate in the absence of diarrhoea. Inherited isolated forms of renal tubular acidosis are not common. However, they can also be a part of a more generalized tubule defect, like in Fanconi syndrome. In recent years more and more gene mutations have been found which are associated with RTA (mutations in the gene SLC4A4, encoding a Na(+)-HCO(3)(-) cotransporter (NBC-1); in the gene SLC4A1, encoding Cl(-)/HCO3(-) exchanger (AE1); in the gene ATP6B1, encoding B1 subunit of H(+)-ATPase; in the gene CA2 encoding carbonic anhydrase II; and others) and allow better understanding of underlying processes of bicarbonate and H(+) transport. Isolated renal tubular acidosis can be frequently acquired due to use of certain drug groups, autoimmune disease or kidney transplantation. As the prevalence of acquired forms of RTA is common, new therapeutic options for the currently used supplementation of oral alkali, are awaited.     

Incidence of Uraemia and Requirements for Maintenance Haemodialysis

The biochemistry laboratory records of a 400-bed general hospital serving a population of about 120,000 showed that during the three-year period 1966-8 inclusive 487 patients had at some stage during their admission a blood urea of 100 mg/100 ml or more. Ninety per cent. were aged 50 or over, 79% were 60 or over, and 52% were 70 or over.The case notes of all patients with renal failure admitted during 1966 and 1967 were examined together with those of patients under 60 admitted during 1968. Three observers agreed about the most likely cause of the renal failure in 90% of patients whose case notes were available, or 74% of the total. The raised blood urea was thought to be due to “prerenal” factors in 60% of the patients, to acute tubular necrosis in 80%, to obstructive uropathy in 12%, and to “intrinsic” renal disease in 20%. Renal failure precipitated by such factors as cardiac failure, chest infections, cerebrovascular accidents, and shock was particularly common in old people.The hospital survey and replies to a questionnaire sent to all general practitioners in the area suggest that in the three-year period 14 patients may have been suitable for treatment by maintenance haemodialysis or renal transplantation. This represents a rate of about 39 per million per year under the age of 60 and 28 per million per year under 50.     

Ocular Findings in Several Metabolic Diseases

Changes in ocular findings have been noted in association with several metabolic diseases.In homocystinuria the crystalline lens in the majority of cases is subluxated inferiorly, while in Marfan''s syndrome the dislocation was upward.In cystinosis, slit-lamp examination reveals numerous gold crystal-like cystine deposits in both the cornea and bulbar conjunctiva.Patients with galactosemia have cataracts of the “oil drop” type, which usually can be seen with an ophthalmoscope even though the opacity is not dense.Eight patients with Lowe''s syndrome who were observed had cataracts, and four of them had severe glaucoma.Three of five patients with glycogen storage disease Type I had yellowish deposits in the macular and paramacular areas, thought to be due to hypercholesterolemia.     

Lactic Acidosis in Diabetes

Lactic acidosis is occasionally responsible for metabolic acidosis in diabetics. It may occur in the presence of normal blood levels of the ketone bodies, and such cases are often described as having “non-ketotic diabetic acidosis.” Lactic acid may contribute to the metabolic acidosis in patients with true diabetic ketoacidosis, but the blood lactate concentrations in these patients are not usually very high. In some patients the ketoacidosis is replaced by a lactic acidosis during treatment. This usually occurs in association with a serious underlying disorder and is associated with a poor prognosis. A transient increase in blood lactate concentration was in fact observed in most patients after the beginning of treatment, but the significance of this finding is uncertain.     

THE TOXIC EFFECTS OF AMPHOTERICIN B IN MAN

Studies of 47 patients with intravenous amphotericin B revealed some impairment of renal function in all cases. Azotemia developed in 46 cases. Microscopic examination in eight cases showed damage to the distal renal tubule. Profound hypokalemia was recognized in two cases; and symptoms suggesting hypokalemia, which were generally ameliorated by potassium administration, were noted in most cases. It is postulated that the initial potassium loss is due to a “tubular leak” and that subsequent potassium depletion leads to further tubular damage.Mild to severe anemia developed in all cases during therapy. Serial red cell indices, bone marrow examinations and red cell survival studies indicated that hemolysis, rather than bone marrow depression, was responsible.The decision to treat, to modify therapy or to terminate treatment must be made on the basis of severity of disease, probability of progression, and renal status.     

The Clinical Significance of Elevated Blood Lactate

Three patients with elevated blood lactate values are described. The first, despite moderate hyperlactatemia of 5.3 mEq./1. and severe acidosis with an arterial blood pH of 6.98, had no “excess lactate”. In a second patient, moderate acidosis with a pH of 7.27 and blood lactate of 7.5 mEq./1., of which 33% was excess lactate, was found to be secondary to tissue hypoxia on an ischemic basis and preceded the onset of clinical shock by four hours. A third patient, diabetic and under treatment with phenformin hydrochloride, presented with many features suggestive of pulmonary embolism, including marked pulmonary hypertension. A diagnosis of idiopathic lactic acidosis was established when the arterial blood pH was found to be 6.77 and a blood lactate value of 14.2 mEq./1., 60% as excess lactate, was discovered in the absence of a demonstrable cause of tissue hypoxia. Exploration of the pulmonary vascular bed showed no sign of mechanical blockage. The diagnostic, therapeutic and prognostic value of measuring blood lactic acid, and of quantitating the proportion circulating as “excess lactate”, is emphasized.     

Dent Disease with mutations in OCRL1

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP(2) 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised.     

Idiopathic Fanconi syndrome with progressive renal failure: a case report and discussion

Fanconi syndrome is a complex of renal tubular dysfunctions defined by glycosuria without diabetes, aminoaciduria, phosphaturia, and renal tubular acidosis. It is often associated with hypokalemia, hypophosphatemia, and rickets or osteomalacia. Although it is usually found in the setting of other well-established non-renal diseases, Fanconi syndrome may present without identifiable etiology or association. Very infrequently a patient with idiopathic Fanconi syndrome will progress to chronic renal failure. This case report details the course of such a patient over the 20 years since his diagnosis and discusses the syndrome's genetic background, clinical features, putative pathophysiology, and therapeutic options, including transplantation.     

Nephrotic Syndrome in Adult Africans in Nairobi

The adult nephrotic syndrome as met with in Nairobi is predominantly encountered in young sophisticated African women, most of whom began to use skin-lightening creams containing mercury before the symptomatic onset of their illness. The particular form of mercury involved is well known to cause the nephrotic syndrome in other circumstances—for example, when applied to the skin in the treatment of psoriasis. In these circumstances the pathogenetic mechanism is thought to be of an idiosyncratic type. The use of mercury-containing skin-lightening creams in the patients studied seemed to be particularly associated with a “minimal-change” (“light-negative”) renal glomerular lesion, this lesion being present in half of the patients. The prognosis in this group of patients seems remarkably good, with 50% entering remission, 77% of these doing so spontaneously on discontinuing the use of the creams.     

Revascularization of the Entire Heart by Internal Mammary Artery Implantation,Epicardiectomy and Free Omental Graft

The indications for and the contraindications to total cardiac revascularization are described on the basis of the author''s experience. The combined operation of internal mammary artery implant, epicardiectomy and free omental graft was performed on 62 patients. Of 45 who did not have angina at rest without exciting cause (Grade I) 39 showed improvement; 32 returned to full-time work, 18 of whom had been unable to work before operation. There were two operative deaths. Among the 17 patients who were “bed-chair cripples” (angina at rest without cause-Grade II), there was a 24% operative mortality (four deaths), but 76% of the survivors had marked improvement. Only one of this group had been working full-time preoperatively; now nine are working full-time.