Priscilla Kincaid-Smith

Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1

Although ultrasound is commonly used for screening subjects at risk of polycystic kidney disease 1 (PKD1), there has been no evaluation of ultrasonographic diagnostic criteria. We used DNA linkage among subjects from 128 sibships within 18 PKD1 families as the basis for an assessment of ultrasound sensitivity. Positive and negative predictive values were calculated to allow assessment of different diagnostic cut-off points in previously undiagnosed cases. Currently used criteria (bilateral cysts with at least two in one kidney) provided good sensitivity (88.5% at age 15-29 years and 100% at 30 years and above) but performance could be improved by less stringent criteria in subjects aged 15-29 years and more stringent criteria in older family members, in whom simple renal cysts are frequent. The presence of at least two renal cysts (unilateral or bilateral) in individuals at risk and younger than 30 years may be regarded as sufficient to establish a diagnosis; among those aged 30-59 years, the presence of at least two cysts in each kidney may be required, and among those aged 60 years and above, at least four cysts in each kidney should be required.

The Effect of Protein Restriction on the Progression of Renal Insufficiency

Dietary protein intake may be an important determinant of the rate of decline in renal function in patients with chronic renal insufficiency. We conducted a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment. The study lasted 18 months and included 64 patients with serum creatinine concentrations ranging from 350 to 1000 micromol per liter. The patients were randomly assigned to follow either a regular diet or an isocaloric protein-restricted diet (0.4 g of protein per kilogram of the body weight per day). Blood-pressure levels and the balance between calcium and phosphate were similar in the two groups. End-stage renal failure developed in 9 of the 33 patients (27 percent) who followed the regular diet during the study, as compared with 2 of the 31 patients (6 percent) who followed the protein-restricted diet (P less than 0.05). The mean (+/- SE) glomerular filtration rate, as measured by the clearance of 51Cr bound to EDTA, fell from 0.25 +/- 0.03 to 0.10 +/- 0.05 ml per second (P less than 0.01) in the group on the regular diet, whereas it fell from 0.23 +/- 0.04 to 0.20 +/- 0.05 ml per second (P not significant) in the group on the protein-restricted diet. We conclude that dietary protein restriction is effective in slowing the rate of progression of chronic renal failure.

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease

It is now clear that mutations of at least two genetic loci can lead to autosomal dominant polycystic kidney disease (ADPKD). We have compared the clinical features of ADPKD caused by mutations at the PKD1 locus (linked to the alpha-globin complex on chromosome 16) with those of disease not linked to the locus (non-PKD1). We identified 18 families (285 affected members) with mutations at PKD1 and 5 families (49 affected individuals) in which involvement of this locus could be dismissed. Non-PKD1 patients lived longer than PKD1 patients (median survival 71.5 vs 56.0 years), had a lower risk of progressing to renal failure (odds ratio 0.35, 95% CI 0.13-0.92), were less likely to have hypertension (odds ratio adjusted for age and family of origin 0.29, 0.11-0.80), were diagnosed at an older age (median 69.1 vs 44.8 years), and had fewer renal cysts at the time of diagnosis. Although most of the PKD1 families were ascertained through clinics treating patients with renal impairment, no non-PKD1 family was identified through this source. Non-PKD1 ADPKD has a much milder phenotype than that linked to PKD1. Partly as a result of this difference in severity, the reported prevalence of this genotype is probably an underestimate.

ANTICOAGULANTS IN "IRREVERSIBLE" ACUTE RENAL FAILURE

Abstract 6 consecutive cases of oliguric renal failure shown histologically to be due to glomerulonephritis or obstructive lesions in arterioles and glomeruli improved considerably following continuous high-dose infusion of heparin, which was given in addition to steroids and immunosuppressive drugs. The prompt improvement in renal function which followed heparin infusion suggests that this method of treatment may have some direct effect on the underlying lesion as has been demonstrated in animals. 2 patients died from diffuse vascular lesions in other organs, but 4 were well at two to nine months after the onset of the renal failure, with blood-urea levels between 23 and 40 mg. per 100 ml.

HISTOLOGICAL DIAGNOSIS OF REJECTION OF RENAL HOMOGRAFTS IN MAN

Abstract Renal microscopy is a valuable guide in the clinical management of patients with cadaveric renal homografts. The main purpose of renal biopsy is to distinguish between homograft rejection and other complications, such as infection which may closely mimic the clinical features of rejection. Renal biopsy permits a clearcut diagnosis of rejection and indicates which patients should receive prompt treatment for rejection. Renal biopsy can also prevent the giving of increased doses of cytotoxic drugs and steroids to patients with infection where they would be particularly dangerous. A normal renal biopsy specimen in 3 patients who showed clinical features suggesting rejection led to exploration and detection of an unsuspected collection of infected material around the ureteric anastomosis. Thrombi in afferent arterioles and glomerular capillaries are prominent in acute rejection and closely resemble those seen in thrombotic thrombocytopenic purpura. Obliterative lesions in interlobular arteries closely resembling those of malignant hypertension seem to result from organisation of mural thrombi.

Deterioration in renal function in association with co-trimoxazole therapy.

Abstract Deterioration in renal function has been observed in sixteen patients in association with co-trimoxazole treatment. This was reversible in most of them, but three patients showed permanent impairment of renal function. In five patients with impaired renal function in whom a modification of the standard dose regimen was used renal function further deteriorated. It is suggested that co-trimoxazole should not be used when the serum-creatinine is above 2 mg. per 100 ml.

Glomerular lesions after renal transplantation.

Significant changes in glomeruli on light microscopy has been observed in 27 of 109 cadaveric renal allografts which functioned beyond 6 months. Tissue was available for study from all but two allografts. The histologic lesions were classified as follows: recurrent glomeruloneophritis, 9 cases (3 focal scierosis, 2 mesangial immunoglobulin A[IgA] disease, 2 mesangiocapillary glomerulonephritis, 1 dense deposit disease, 1 familial nephritis); de novo glomerulonephritis, 1 case (diffuse proliferative glomerulonephritis with crescents); and glomerular change of uncertain etiology, 17 cases (10 mesangiocapillary, 5 focal scierosis, 1 focal proliferative and 1 mesangial proliferative). These lesions were not distinguishable on light, fluorescent and electron microscopy from those in patients with spontaneous renal disease. All patients with glomerular lesions had proteinuria, and all but 3 had microscopic hematuria. Glomerular lesions were not significantly associated with early clinical rejection episodes or HLA compatibility. Presensitization of HLA antigens was significantly related to the occurence of a nonrecurrent glomerular lesion. Vescoureteral reflux was significantly more frequent in those with glomerular change (14 of 24) than in those without (13 of 48). Glomerular lesions were associated with a higher rate of graft loss due to renal transplant failure; renal function in survivors was significantly worse than in those without glomerular lesions.

Risks of vesicoureteric reflux in the transplanted kidney.

The risk to the transplanted kidney of vesicoureteric reflux was evaluated in 150 consecutive first cadaveric renal allografts surviving for over three months. Of the 119 (79 per cent) allografts studied by micturating cystography 29 (24 per cent) were shown to reflux. The presence of reflux was associated with urine leakage and reoperation, and with ureteric insertion involving a short intramural tunnel. Graft failure (graft nephrectomy or death from renal failure) occurred in 14 of 29 refluxing grafts as compared to 14 failures in 90 nonrefluxing grafts (P less than 0.01). Graft failure in the refluxing group was typically slow, and commonly associated with proteinuria, microscopic hematuria, hypertension and a biopsy appearance of mesangiocapillary glomerular change. Urinary infection, though frequent (69 per cent), was not more common in the group with than in that without reflux. Vesicoureteric reflux is an important cause of late renal-graft failure.

PATHOGENESIS OF THE RENAL LESION ASSOCIATED WITH THE ABUSE OF ANALGESICS

Abstract Renal papillary necrosis is the primary lesion in the kidney in patients who take large quantities of analgesic drugs. Morbid-anatomical studies and biopsy and radiological data show that the cortical changes of so-called chronic interstitial nephritis are the result of atrophy which develops as a direct consequence of the papillary necrosis. It is suggested that precipitation of excretion products of analgesic drugs due to the high urinary concentration in the loops of Henle may initiate the pathological lesions which lead to papillary necrosis.

Papillary Necrosis in Rats Caused by Aspirin and Aspirin-containing Mixtures

Nearly half the rats gavage-fed with aspirin and aspirin-containing mixtures developed papillary necrosis in 20 weeks. This incidence is similar to that found in rats on A.P.C. mixtures with high and low concentrations of p-chloracetanilide, an impurity of phenacetin. Aspirin alone produced necrosis in 7 out of 19 rats (36·8%) whereas phenacetin in the same dose had failed to cause any renal damage over six to nine months. If these results also apply to man they suggest that aspirin and not phenacetin may be the major factor in analgesic nephropathy in patients taking A.P.C. mixtures. An augmented clearance of aspirin appeared to afford some protection to the medulla, and it is suggested that this observation may have important clinical and epidemiological applications.