E pluribus unum: The riddle of focal segmental glomerulosclerosis

A recent consensus conference proposed a new classification for focal segmental glomerulosclerosis (FSGS). Five patterns have been defined: FSGS not otherwise specified, perihilar variant, cellular variant, tip variant, and collapsing variant. In light of the multiplicity of classification schemes in use, the promise of a rational and uniform scheme for FSGS pathology is most welcome. This approach has worked extremely well for the classification of lupus nephritis. It does not necessarily mean, however, that this new classification scheme will help to select treatment protocols according to histopathologic subsets of FSGS. In fact, one renal biopsy examination may show multiple variants and this classification, despite many merits, still lumps categories that should be split and splits categories that should be lumped together. It has become clear that despite its histologic diversity FSGS begins as a podocyte disease that progresses from a cellular to a scar lesion. Recent years have brought about astonishing insight into the complex molecular array of proteins forming the slit diaphragm between podocyte foot processes, a narrow space essential for restricting glomerular permeability to albumin. Concentrating on the podocyte rather than on the glomerular tuft is helpful for abolishing the classic distinction between primary versus secondary forms of FSGS, a distinction that crumbles away with each new evidence of genetic, ischemic, or viral etiologies of FSGS, despite similar lesions. In fact, recent studies focusing on the podocyte changes that occur in various subsets of FSGS have unraveled the striking phenomena of podocyte dedifferentiation and transdifferentiation along with differential expression of cyclin-dependent kinase inhibitors. Interestingly, the latter showed that expression of cyclin-dependent kinase inhibitors p21 and proliferation marker Ki-67 are the same in cellular FSGS, collapsing glomerulopathy, and human immunodeficiency virus-associated FSGS. Taken together these findings lead to a reassuring unitary interpretation of the pluralistic appearance of FSGS by histopathology. Clearly, further studies of the podocyte will lead to improved understanding of FSGS and to improved classification schemes that are grounded in molecular understanding of glomerular injury and that will guide the clinician in the choice of treatment and prognosis.     

Protracted anuria due to active vasoconstriction in primary or secondary malignant hypertension

Anuria complicated the malignant phase of hypertension in twelve patients (ten males and two females). Five were black; five had primary hypertension; one had HBs virus angiitis; the six remaining cases suffered from previously documented renal disease, including two with Berger's disease. Renal angiography showed interruption of renal blood flow as far as the main branches of the renal artery and/or a false impression of 'cortical necrosis' and of 'renal infarcts'. In contrast, renal biopsy did not show irreversible vascular damage. Thus, anuria was mainly functional and due to active renal vasoconstriction. This was confirmed by the subsequent course; diuresis resumed after 1 week to 24 months of dialysis. Repeat angiography in six cases showed recovery of renal circulation and disappearance of 'cortical infarcts', even when plasma renin activity remained elevated and hypertension was not controlled. In one case captopril induced a new reversible episode of anuria. These observations suggest that active vasoconstriction with prolonged anuria might be due to some vasoconstrictive substance other than angiotensin II.     

In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys

The nail-patella syndrome (NPS) is characterized by nail and bone abnormalities, associated with glomerular involvement in approximately 40% of patients. Typical glomerular changes consist of fibrillar material in the irregularly thickened glomerular basement membrane. NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family. Mice with homozygous inactivation of the gene exhibit nail and skeletal defects, similar to those observed in patients, associated with glomerular abnormalities. Strong reduction in the glomerular expression of the alpha3 and alpha4 chains of type IV collagen, and of podocin and CD2AP, two podocyte proteins critical for glomerular function, has been observed in Lmx1b null mice. The expression of these proteins appeared to be regulated by Lmx1b. To determine whether these changes in podocyte gene expression are involved in the development of NPS nephropathy, using immunohistological techniques, we analyzed the podocyte phenotype and the renal distribution of type IV collagen chains in the kidneys of seven NPS patients with severe glomerular disease. We also examined the nature of the fibrillar material present within the glomerular extracellular matrix. The glomerular basement membrane fibrillar material was specifically labeled with anti-type III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the alpha3 and alpha4 chains of type IV collagen, and of podocin and CD2AP, was found to be normal in the seven patients. These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients.     

Malignant arterial hypertension in periarteritis nodosa. Incidence, clinicobiologic parameters and prognosis based on a series of 165 cases

The authors studied clinical and biological data occurring in 165 patients observed during 23 years and afflicted with polyarteritis nodosa. Hypertension was present in 52 patients (31.5%) and seven of them suffered from malignant hypertension (4%). Mean age of patients (6 male, 1 female), with malignant hypertension was 38 +/- years old. Mean follow up was 49 +/- 28 months including 26 +/- 21 months after discontinuation of treatment of polyarteritis nodosa. Malignant hypertension occurred during the first year of evolution of polyarteritis nodosa. Renal insufficiency was present in 5 of 7 patients. Proteinuria was greater than 1 gr/d in 4 cases. Renal arteriography was performed in 6 patients and showed in every case renal ischemia and microaneurysms in five. In 4 patients measurements of plasma renin activity and of aldosterone were obtained. A stimulation of those hormones was demonstrated. Some symptoms of polyarteritis nodosa were present with a high incidence in case of malignant hypertension: digestive signs (6/7), orchitis (3/6). HBs antigen was present in 6 cases and hepatitis in 5. Captopril was effective in every case, alone or associated with other treatments. Follow up of hypertension went from 8 months to 4 years. At present time 6 patients are alive and one is lost of follow up. A treatment is necessary in 6 of 7 patients. Creatininemia is greater than 300 micromol/l in 4 patients. A successful kidney transplantation was performed in one case. Our study shows a close relation between malignant hypertension observed in polyarteritis nodosa, vascular nephropathy, digestive and urologic signs. Hepatitis B virus could be responsible of those manifestations.     

Cholesterol crystal embolism: diagnosis and treatment

Cholesterol crystal embolization (CCE) is a dreaded complication of radiology, vascular surgery, and/or anticoagulation in patients with atherosclerosis and ulcerated aortic plaques. It also represents a cause of early graft failure and of poor results of renal artery surgery. Crystals lodge in small caliber renal arteries, where they induce early, transitory thrombosis followed by delayed, definitive obstruction by endarteritis, accompanied by evidence of inflammation and eosinophilia. Massive CCE leads to early oligoanuria. In subacute forms, renal insufficiency is often delayed by weeks or months following the triggering event. A third, chronic subset of CCE is easily mistaken for atherosclerotic renal ischemia and/or nephrosclerosis. The kidney is rarely the sole organ involved in acute/subacute forms, in which the central nervous system, the coronary arteries, the spinal cord, and the mesenteric and pancreatic blood supply compromise represent the main causes of death. Cutaneous, retinal, and muscle involvement allow diagnosis by inspection or scarcely invasive biopsies in about 80% of cases, whereas renal biopsy as the only diagnostic procedure is required in 20% of cases. Prevention is based on avoidance of endovascular radiology maneuvers, vascular surgery, and excess anticoagulation in atherosclerotic patients. Treatment of acute/subacute forms of renal insufficiency consisting of stopping anticoagulation and forbidding any new radiologic and/or vascular surgery procedure; treating hypertension with angiotensin 2 antagonists and vasodilators, strict volemic control by loop diuretics and ultrafiltration, along with parenteral nutrition and prednisone, has been credited with improved outcome. Iloprost may obtain favorable results. Statins definitely ameliorate the renal and patient's prognosis.     

Renal transplantation and immunological abnormalities in thrombotic microangiopathy of adults: report of 5 cases.

Renal transplantation was performed in five adult patients with thrombotic microangiopathy, three of whom had had a bilateral nephrectomy prior to transplantation. The graft remained functional in three patients 72, 18, and 12 months after transplantation. One patient developed a thrombosis of the renal artery and one patient died from infection. There was no clinical or histological evidence of recurrence of thrombotic microangiopathy in the five patients after transplantation. Immunological investigations were performed in four of five patients before transplantation: C3 and C1q levels were low in two patients; serum C3-splitting activity and circulating immune complexes were present in all four patients and remained unchanged on haemodialysis and/or after bilateral nephrectomy. Complement abnormalities and immune complexes were not detected in the three patients with successful renal transplantation.     

Minor haemoglobin fractions in uraemic and in diabetic patients

Using a high resolution automated chromatographic method, the levels of the different minor haemoglobins Hb A1a, A1b, and A1c were measured in 20 healthy controls, in 20 patients with chronic renal failure, in 20 uraemic patients on intermittent haemodialysis, and in 20 insulin-dependent diabetic patients. In uraemic non haemodialysed patients, the levels of the three minor fractions were increased significantly. The two fractions Hb A1b and A1c were normalised subsequent to haemodialysis, whereas the level of Hb A1a was higher in the haemodialysed than in the uraemic non haemodialysed group. In both groups of uraemic patients, no correlation was found between the minor Hb fractions and the corresponding serum creatinine, uric acid, urea, phosphorus, bicarbonate and blood glucose levels. In diabetic patients, the three minor fractions were increased. As expected, Hb A1c and glucose concentrations were tightly correlated. No correlation was found between blood glucose levels and Hb A1a, whereas a correlation existed between blood glucose levels and Hb A1b. It is concluded that the increase of minor haemoglobin fractions in renal failure does not only reflect the glucose intolerance. Renal failure itself causes an increase of the three minor fractions. Overall assay of the minor haemoglobin components (Hb A1) may lead to misinterpretation in case of diabetic patients with chronic renal failure.     

Utilisation of pipemidic acid as antibiotic in patients with renal failure insufficiency. Kinetics of serum and urinary concentrations (author's transl)]

In 23 chronic renal patients serum and urinary concentrations of pipemidic acid were studied, the drug being given orally for 3 to 105 days. In 13 non-dialyzed patients, whose GFR varied from 4.5 to 36 ml/mn the dosage was 11.2 to 30 mg/kg/day. Maximum serum concentrations were comprised between 6 and 29 micrograms/ml. In 2 patients minor clinical side-effects indicated a maximum tolerance level of 25 micrograms/ml. Urinary concentrations remained elevated in spite of severe renal failure. In 10 hemodialyzed patients maximum predialysis levels varied from 5.6 to 28 micrograms/ml. No side-effects were noticed. The dialysance of pipemidic acid was high, due to a low molecular weight and to a binding to proteins which seems to be lower in uremics than in normal subjects. We conclude that pipemidic acid can be utilized in chronic renal patients, in taking advantage of low GFR's for obtaining serum bactericidal concentrations on susceptible organisms.     

Papillary Necrosis in Renal Allografts—Report of 2 cases

Summary: Two patients are reported in whom early and irreversible renal allo-graft rejection was associated with passage of necrotic papillary material in the urine. Evidence is presented for a causal relationship between rejection and medullary necrosis. Passage of a papilla is regarded as a definite indication for graft exploration.